@article {pmid40364858,
year = {2025},
author = {Doroszkiewicz, J and Winkel, I and Mroczko, B},
title = {Comparative analysis of neuroinflammatory pathways in Alzheimer's disease, Parkinson's disease, and multiple sclerosis: insights into similarities and distinctions.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1579511},
pmid = {40364858},
issn = {1662-4548},
abstract = {Neurodegenerative diseases, contributing to the significant socioeconomic burden due to aging society, are gaining increasing interest. Despite each disease having different etiologies, neuroinflammation is believed to play a crucial role in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). In addition to the pathogenic function of inflammation in the brain there is growing evidence that immune responses are essential for neuroregeneration. This review compares and contrasts the neuroinflammatory pathways that selected neurodegenerative diseases share and have in common. In AD, tau tangles and beta-amyloid plaques cause microglia and astrocytes to become activated in an inflammatory response. Alpha-synuclein aggregation stimulate neuroinflammation in Parkinson's disease, especially in the substantia nigra. In Multiple Sclerosis an autoimmune attack on myelin is connected to inflammation via invading immune cells. Commonalities include the release of pro-inflammatory mediators like cytokines and activation of signaling pathways such as NF-κB and MAPK. Comprehending these common routes is essential for discovering early diagnostic possibilities for the diseases and possible tailored treatments. Our work underscores the potential for insights into disease mechanisms. Identifying common targets offers promise for advancing our understanding and potential future treatment approaches across these debilitating disorders.},
}

@article {pmid40363853,
year = {2025},
author = {Simakov, A and Chhor, S and Ismaili, L and Martin, H},
title = {Nrf2 Activation and Antioxidant Properties of Chromone-Containing MTDLs for Alzheimer's Disease Treatment.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092048},
pmid = {40363853},
issn = {1420-3049},
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism ; *Antioxidants/pharmacology/chemistry ; Humans ; *Chromones/pharmacology/chemistry ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Ligands ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; Antioxidant Response Elements ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide and imposing a significant social and economic burden. Despite extensive research, there is still no effective cure for this disease. AD is multifactorial and involves multiple etiopathogenic mechanisms, one of which is oxidative stress. Consequently, the Nrf2/ARE pathway, which regulates the expression of cellular defense genes, including those for antioxidant enzymes, is considered to be a prospective therapeutic target for AD. Meanwhile, multitarget-directed ligands (MTDLs) are a promising approach for developing effective AD medications. In this regard, we evaluated the antioxidant potential of eight chromone-containing MTDLs in vitro, including Nrf2 transcriptional activation potencies, Nrf2/ARE downstream genes activation, and antioxidant effects in vitro. All tested compounds effectively activated the Nrf2/ARE pathway. Notably, compounds 4b, 4c, 4f, and 4h demonstrated the highest Nrf2 activation potencies, while compounds 4b, 4c, 4d, and 4g significantly induced the expression of Nrf2-target antioxidant genes, specifically NQO1 and HO1. Additionally, compound 4d exhibited a significant antioxidant effect in vitro. These findings encourage further investigation of the studied compounds, with particular emphasis on compound 4d as the most promising candidate.},
}

*NF-E2-Related Factor 2/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism
*Antioxidants/pharmacology/chemistry
Humans
*Chromones/pharmacology/chemistry
Oxidative Stress/drug effects
Signal Transduction/drug effects
Ligands
NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism
Antioxidant Response Elements

@article {pmid40363835,
year = {2025},
author = {Kim, TK and Hong, JM and Cho, Y and Jeon, Y and Cho, H and Lee, J and Kim, J and Kim, KH and Kim, IC and Han, SJ and Oh, H and Jo, DG and Yim, JH},
title = {Synthesis and Biological Evaluation of Novel Ramalin Derivatives as Multi-Target Agents for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092030},
pmid = {40363835},
issn = {1420-3049},
support = {KOPRI PE25160//Korea Polar Research Institute/ ; RS-2021-KS211513//Ministry of Oceans and Fisheries/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Antioxidants/pharmacology/chemical synthesis/chemistry ; tau Proteins/metabolism ; Animals ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Oxidative Stress/drug effects ; Mice ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, amyloid-beta (Aβ) accumulation, and tau protein hyperphosphorylation. In this study, we synthesized novel Ramalin derivatives and evaluated their therapeutic potential against AD, focusing on antioxidant, anti-inflammatory, and neuroprotective activities. RA-2OMe, RA-4OMe, RA-2CF3, and RA-4OCF3 showed strong antioxidant effects, while RA-2OMe exhibited potent NO and NLRP3 inhibition (~20%). RA-NAP, RA-PYD, and RA-2Q showed moderate anti-inflammatory activity. BACE-1 inhibition was significant in RA-3CF3, RA-NAP, and RA-PYD, with IC50 values lower than that of positive control, indicating greater inhibitory potency. RA-NAP and RA-PYD effectively inhibited both Aβ and tau aggregation, highlighting their multi-target potential for AD therapy. These findings indicate that Ramalin derivatives exhibit potential for multi-target activity in AD treatment. However, further studies on their pharmacokinetics, in vivo efficacy, and long-term safety are required to confirm their therapeutic applicability.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
Amyloid beta-Peptides/metabolism
*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
Antioxidants/pharmacology/chemical synthesis/chemistry
tau Proteins/metabolism
Animals
Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry
Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
Oxidative Stress/drug effects
Mice
Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism

@article {pmid40363789,
year = {2025},
author = {Küpeli Akkol, E and Karatoprak, GŞ and Dumlupınar, B and Bahadır Acıkara, Ö and Arıcı, R and Yücel, Ç and Aynal, LC and Sobarzo Sánchez, E},
title = {Stilbenes Against Alzheimer's Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30091982},
pmid = {40363789},
issn = {1420-3049},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Stilbenes/chemistry/therapeutic use/pharmacology/chemical synthesis ; Animals ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Drug Delivery Systems ; Amyloid beta-Peptides/metabolism ; },
abstract = {This review covers preclinical studies of stilbene derivative compounds (both natural and synthetic) with potential preventive and therapeutic effects against Alzheimer's disease (AD). AD is a worldwide neurodegenerative disease characterized by the destruction of nerve cells in the brain and the loss of cognitive function due to aging. Stilbenes are a unique class of natural phenolic compounds distinguished by a C6-C2-C6 (1,2-diphenylethylene) structure and two aromatic rings connected by an ethylene bridge. Stilbenes' distinct features make them an intriguing subject for pharmacological research and development. Several preclinical studies have suggested that stilbenes may have neuroprotective effects by reducing Aβ generation and oligomerization, enhancing Aβ clearance, and regulating tau neuropathology through the prevention of aberrant tau phosphorylation and aggregation, as well as scavenging reactive oxygen species. Synthetic stilbene derivatives also target multiple pathways involved in neuroprotection and have demonstrated promising biological activity in vitro. However, some properties of stilbenes, such as sensitivity to physiological conditions, low solubility, poor permeability, instability, and low bioavailability, limit their usefulness in clinical applications. To address this issue, current investigations have developed new drug delivery systems based on stilbene derivative molecules. This review aims to shed light on the development of next-generation treatment strategies by examining in detail the role of stilbenes in Alzheimer's pathophysiology and their therapeutic potential.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Stilbenes/chemistry/therapeutic use/pharmacology/chemical synthesis
Animals
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
*Drug Delivery Systems
Amyloid beta-Peptides/metabolism

@article {pmid40363158,
year = {2025},
author = {Cardinali, L and Mariano, V and Rodriguez-Duarte, DO and Tobón Vasquez, JA and Scapaticci, R and Crocco, L and Vipiana, F},
title = {Early Detection of Alzheimer's Disease via Machine Learning-Based Microwave Sensing: An Experimental Validation.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {9},
pages = {},
doi = {10.3390/s25092718},
pmid = {40363158},
issn = {1424-8220},
support = {THERAD - Microwave Theranostics for Alzheimer's Disease//Compagnia di San Paolo/ ; Piano Nazionale di Ripresa e Resilienza (PNRR) - MISSIONE 4 COMPONENTE 2, INVESTIMENTO 1.4 - D.D. 1032 17/06/2022, CN00000022//European Union Next-Generation EU/ ; Microwave Imaging and Detection powered by Artificial Intelligence for Medical and Industrial Applications (DM 1062/21)//Ministero dell'università e della ricerca/ ; },
mesh = {*Alzheimer Disease/diagnosis/cerebrospinal fluid ; Humans ; *Microwaves ; *Machine Learning ; Early Diagnosis ; Algorithms ; *Biosensing Techniques/methods ; Biomarkers/cerebrospinal fluid ; },
abstract = {The early diagnosis of Alzheimer's disease remains an unmet medical need due to the cost and invasiveness of current methods. Early detection would ensure a higher quality of life for patients, enabling timely and suitable treatment. We investigate microwave sensing for low-cost, non-intrusive early detection and assessment of Alzheimer's disease. This study is based on the emerging evidence that the electromagnetic properties of cerebrospinal fluid are affected by abnormal concentrations of proteins recognized as early-stage biomarkers. We design a conformal six-element antenna array placed on the upper portion of the head, operating in the 500 MHz to 6.5 GHz band. It measures scattering response due to changes in the dielectric properties of intracranial cerebrospinal fluid. A multi-layer perceptron network extracts the diagnostic information. Data classification consists of two steps: binary classification to identify the disease presence and multi-class classification to evaluate its stage. The algorithm is trained and validated through controlled experiments mimicking various pathological severities with an anthropomorphic multi-tissue head phantom. Results support the feasibility of the proposed method using only amplitude data and lay the foundation for more extensive studies on microwave sensing for early Alzheimer's detection.},
}

*Alzheimer Disease/diagnosis/cerebrospinal fluid
Humans
*Microwaves
*Machine Learning
Early Diagnosis
Algorithms
*Biosensing Techniques/methods
Biomarkers/cerebrospinal fluid

@article {pmid40362738,
year = {2025},
author = {Cerullo, M and Armeli, F and Mengoni, B and Menin, M and Crudeli, ML and Businaro, R},
title = {Curcumin Modulation of the Gut-Brain Axis for Neuroinflammation and Metabolic Disorders Prevention and Treatment.},
journal = {Nutrients},
volume = {17},
number = {9},
pages = {},
doi = {10.3390/nu17091430},
pmid = {40362738},
issn = {2072-6643},
mesh = {*Curcumin/pharmacology/therapeutic use ; Humans ; *Metabolic Diseases/prevention & control/drug therapy ; Gastrointestinal Microbiome/drug effects ; Animals ; *Neuroinflammatory Diseases/prevention & control/drug therapy ; *Brain/drug effects ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; *Brain-Gut Axis/drug effects ; Inflammation/prevention & control ; },
abstract = {Curcumin, a polyphenolic compound derived from Curcuma longa, has gained significant attention for its potential therapeutic benefits, particularly counteracting inflammation, oxidative stress, and metabolic disorders. Its chemical structure, featuring conjugated double bonds between two aromatic rings, allows it to act as an electron donor, thereby mitigating free radical formation. Despite its poor solubility in water, curcumin is stable in acidic environments and undergoes significant metabolism in both the liver and the gut. Intestinal microbiota, particularly at the colon level, further metabolizes curcumin into several derivatives, including dihydrocurcumin and tetrahydrocurcumin, which exhibit antioxidant and anti-inflammatory properties. Studies suggest that curcumin can reduce body mass index (BMI) and improve other body composition parameters, especially when used in combination with lifestyle changes, though its bioavailability is low due to its rapid metabolism and the resulting low blood concentration. In obesity, dysfunctional adipose tissue remodeling and chronic inflammation play critical roles in the development of metabolic complications. Curcumin's anti-inflammatory properties are related to the inhibition of the NF-κB pathway, leading to the reduction in inflammatory markers in adipocytes and macrophages. Additionally, curcumin modulates oxidative stress by activating the NRF2 pathway, enhancing cellular antioxidant defenses. Emerging evidence also supports curcumin's potential in improving gut health by modulating microbiota composition, enhancing intestinal barrier function, and reducing systemic inflammation. This interaction with the gut-brain axis highlights the broader implications of curcumin in neuroprotection, as it positively affects cognitive function and mitigates neuroinflammation in neurodegenerative diseases like Alzheimer's. disease. Thus, curcumin holds promise as a multifaceted agent in the management of obesity and associated diseases.},
}

*Curcumin/pharmacology/therapeutic use
Humans
*Metabolic Diseases/prevention & control/drug therapy
Gastrointestinal Microbiome/drug effects
Animals
*Neuroinflammatory Diseases/prevention & control/drug therapy
*Brain/drug effects
Oxidative Stress/drug effects
Anti-Inflammatory Agents/pharmacology
*Brain-Gut Axis/drug effects
Inflammation/prevention & control

@article {pmid40362609,
year = {2025},
author = {Qin, C and Li, D and Zhang, J and Yin, Z and Li, F},
title = {Scorpion Venom Heat-Resistant Synthetic Peptide Alleviates Neuronal Necroptosis in Alzheimer's Disease Model by Regulating Lnc Gm6410 Under PM2.5 Exposure.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094372},
pmid = {40362609},
issn = {1422-0067},
support = {No. LJKZ0844//Liaoning Provincial Department of Education Research Foundation of China/ ; },
mesh = {Animals ; *Particulate Matter/adverse effects/toxicity ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics/etiology ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Necroptosis/drug effects ; *RNA, Long Noncoding/genetics/metabolism ; Disease Models, Animal ; *Scorpion Venoms/pharmacology/chemistry ; *Peptides/pharmacology ; Humans ; Male ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; },
abstract = {Recent epidemiological studies have indicated that exposure to particulate matter with an aerodynamic diameter of 2.5 μm or less in the ambient air (PM2.5) is significantly associated with an elevated risk of developing Alzheimer's disease (AD) and its progression. Scorpion venom heat-resistant synthetic peptide (SVHRSP) exhibits anti-inflammatory and neuroprotective properties. However, the exact ways in which SVHRSP mitigates the progression of AD induced by PM2.5 are still unknown. Long non-coding RNA (lncRNA) plays a crucial role in various biological processes. Necroptosis, a form of programmed cell death, has garnered considerable attention in recent years. This study aims to investigate whether Lnc Gm16410 and neuronal necroptosis are involved in PM2.5-exacerbated AD progression and the mechanisms of SVHRSP in alleviating this process. Through the establishment of a PM2.5 exposure model in AD mice and an in vitro model, it was found that PM2.5 exposure could promote necroptosis and the down-regulation of Lnc Gm16410, thereby promoting the progression of AD. Behavioral tests showed that SVHRSP alleviated cognitive impairment in PM2.5-induced AD mice. WB, qRT-PCR, and other molecular biological assays indicate that Lnc Gm16410 regulates neuronal necroptosis under PM2.5 exposure via the p38 MAPK pathway. SVHRSP is a potential regulator of AD progression by regulating Lnc Gm16410 to alleviate PM2.5 exposure-induced necroptosis. These findings offer new insights into the mechanism through which PM2.5 exposure accelerates the progression of AD, examined from the perspective of LncRNA. Furthermore, we offer new targets for the treatment and prevention of AD following PM2.5 exposure by investigating the mechanism of action of SVHRSP in alleviating AD.},
}

Animals
*Particulate Matter/adverse effects/toxicity
*Alzheimer Disease/drug therapy/metabolism/pathology/genetics/etiology
Mice
*Neurons/drug effects/metabolism/pathology
*Necroptosis/drug effects
*RNA, Long Noncoding/genetics/metabolism
Disease Models, Animal
*Scorpion Venoms/pharmacology/chemistry
*Peptides/pharmacology
Humans
Male
Mice, Inbred C57BL
Neuroprotective Agents/pharmacology

@article {pmid40362589,
year = {2025},
author = {Ontawong, A and Nehra, G and Maloney, BJ and Vaddhanaphuti, CS and Bauer, B and Hartz, AMS},
title = {N-Acetylcysteine Attenuates Aβ-Mediated Oxidative Stress, Blood-Brain Barrier Leakage, and Renal Dysfunction in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094352},
pmid = {40362589},
issn = {1422-0067},
support = {1R01NS133250-24A1/NH/NIH HHS/United States ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Blood-Brain Barrier/drug effects/metabolism ; *Acetylcysteine/pharmacology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; Mice, Transgenic ; Disease Models, Animal ; Aldehydes/metabolism ; Male ; Antioxidants/pharmacology ; Brain/metabolism/drug effects ; Kidney/drug effects/metabolism ; S100 Calcium Binding Protein beta Subunit/blood ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology and is closely linked to oxidative stress, which contributes to blood-brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg/kgDiet NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other Aβ-related pathologies by reducing oxidative stress.},
}

Animals
*Oxidative Stress/drug effects
*Blood-Brain Barrier/drug effects/metabolism
*Acetylcysteine/pharmacology
*Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/metabolism/drug therapy
Mice, Transgenic
Disease Models, Animal
Aldehydes/metabolism
Male
Antioxidants/pharmacology
Brain/metabolism/drug effects
Kidney/drug effects/metabolism
S100 Calcium Binding Protein beta Subunit/blood

@article {pmid40362488,
year = {2025},
author = {Volloch, V and Rits-Volloch, S},
title = {Alzheimer's Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094252},
pmid = {40362488},
issn = {1422-0067},
support = {NIH R21 GM056179; NIH RO1 AR036819/GF/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology/etiology ; Humans ; *Neurons/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Amyloid beta-Protein Precursor/metabolism ; Proteolysis ; *Peptide Fragments/metabolism ; },
abstract = {The present Perspective analyzes the remarkable evolution of the Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory of Alzheimer's disease (AD) since its inception a few years ago, as reflected in the diminishing role of amyloid-beta (Aβ) in the disease. In the initial iteration of the ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. The neuronal ISR, in turn, activates the AβPP-independent production of its C99 fragment that is processed into iAβ, which drives the disease. The second iteration of the ACH2.0 stemmed from the realization that AD is, in fact, a disease of the sustained neuronal ISR. It introduced two categories of AD-conventional and unconventional-differing mainly in the manner of their causation. The former is caused by the neuronal ISR triggered by AβPP-derived iAβ, whereas in the latter, the neuronal ISR is elicited by stressors distinct from AβPP-derived iAβ and arising from brain trauma, viral and bacterial infections, and various types of inflammation. Moreover, conventional AD always contains an unconventional component, and in both forms, the disease is driven by iAβ generated independently of AβPP. In its third, the current, iteration, the ACH2.0 posits that proteolytic production of Aβ is suppressed in AD-affected neurons and that the disease is driven by C99 generated independently of AβPP. Suppression of Aβ production in AD seems an oxymoron: Aβ is equated with AD, and the later is inconceivable without the former in an ingrained Amyloid Cascade Hypothesis (ACH)-based notion. But suppression of Aβ production in AD-affected neurons is where the logic leads, and to follow it we only need to overcome the inertia of the preexisting assumptions. Moreover, not only is the generation of Aβ suppressed, so is the production of all components of the AβPP proteolytic pathway. This assertion is not a quantum leap (unless overcoming the inertia counts as such): the global cellular protein synthesis is severely suppressed under the neuronal ISR conditions, and there is no reason for constituents of the AβPP proteolytic pathway to be exempted, and they, apparently, are not, as indicated by the empirical data. In contrast, tau protein translation persists in AD-affected neurons under ISR conditions because the human tau mRNA contains an internal ribosomal entry site in its 5'UTR. In current mouse models, iAβ derived from AβPP expressed exogenously from human transgenes elicits the neuronal ISR and thus suppresses its own production. Its levels cannot principally reach AD pathology-causing levels regardless of the number of transgenes or the types of FAD mutations that they (or additional transgenes) carry. Since the AβPP-independent C99 production pathway is inoperative in mice, the current transgenic models have no potential for developing the full spectrum of AD pathology. What they display are only effects of the AβPP-derived iAβ-elicited neuronal ISR. The paper describes strategies to construct adequate transgenic AD models. It also details the utilization of human neuronal cells as the only adequate model system currently available for conventional and unconventional AD. The final alteration of the ACH2.0, introduced in the present Perspective, is that AβPP, which supports neuronal functionality and viability, is, after all, potentially produced in AD-affected neurons, albeit not conventionally but in an ISR-driven and -compatible process. Thus, the present narrative begins with the "omnipotent" Aβ capable of both triggering and driving the disease and ends up with this peptide largely dislodged from its pedestal and retaining its central role in triggering the disease in only one, although prevalent (conventional), category of AD (and driving it in none). Among interesting inferences of the present Perspective is the determination that "sporadic AD" is not sporadic at all ("non-familial" would be a much better designation). The term has fatalistic connotations, implying that the disease can strike at random. This is patently not the case: The conventional disease affects a distinct subpopulation, and the basis for unconventional AD is well understood. Another conclusion is that, unless prevented, the occurrence of conventional AD is inevitable given a sufficiently long lifespan. This Perspective also defines therapeutic directions not to be taken as well as auspicious ways forward. The former category includes ACH-based drugs (those interfering with the proteolytic production of Aβ and/or depleting extracellular Aβ). They are legitimate (albeit inefficient) preventive agents for conventional AD. There is, however, a proverbial snowball's chance in hell of them being effective in symptomatic AD, lecanemab, donanemab, and any other "…mab" or "…stat" notwithstanding. They comprise Aβ-specific antibodies, inhibitors of beta- and gamma-secretase, and modulators of the latter. In the latter category, among ways to go are the following: (1) Depletion of iAβ, which, if sufficiently "deep", opens up a tantalizing possibility of once-in-a-lifetime preventive transient treatment for conventional AD and aging-associated cognitive decline, AACD. (2) Composite therapy comprising the degradation of C99/iAβ and concurrent inhibition of the neuronal ISR. A single transient treatment could be sufficient to arrest the progression of conventional AD and prevent its recurrence for life. Multiple recurrent treatments would achieve the same outcome in unconventional AD. Alternatively, the sustained reduction/removal of unconventional neuronal ISR-eliciting stressors through the elimination of their source would convert unconventional AD into conventional one, preventable/treatable by a single transient administration of the composite C99/iAβ depletion/ISR suppression therapy. Efficient and suitable ISR inhibitors are available, and it is explicitly clear where to look for C99/iAβ-specific targeted degradation agents-activators of BACE1 and, especially, BACE2. Directly acting C99/iAβ-specific degradation agents such as proteolysis-targeting chimeras (PROTACs) and molecular-glue degraders (MGDs) are also viable options. (3) A circumscribed shift (either upstream or downstream) of the position of transcription start site (TSS) of the human AβPP gene, or, alternatively, a gene editing-mediated excision or replacement of a small, defined segment of its portion encoding 5'-untranslated region of AβPP mRNA; targeting AβPP RNA with anti-antisense oligonucleotides is another possibility. If properly executed, these RNA-based strategies would not interfere with the protein-coding potential of AβPP mRNA, and each would be capable of both preventing and stopping the AβPP-independent generation of C99 and thus of either preventing AD or arresting the progression of the disease in its conventional and unconventional forms. The paper is interspersed with "validation" sections: every conceptually significant notion is either validated by the existing data or an experimental procedure validating it is proposed.},
}

*Alzheimer Disease/metabolism/pathology/etiology
Humans
*Neurons/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Amyloid beta-Protein Precursor/metabolism
Proteolysis
*Peptide Fragments/metabolism

@article {pmid40362451,
year = {2025},
author = {Park, CK and Choi, SJ and Kim, CR and Shin, HR and Shin, EC and Kim, YJ and Cho, TJ and Shin, DH and Kim, JK},
title = {Ethanolic Extract of Rosa rugosa Roots and Its Bioactive Compound, Oleamide, Prevented Amyloid β-Induced Oxidative Stress and Improved Behavioral Tests in Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094214},
pmid = {40362451},
issn = {1422-0067},
support = {RS-2024-00332492//the Ministry of Food and Drug Safety of South Korea/ ; NRF-2022R1A4A3033775//the National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science and ICT, MSIT)/ ; RS-2024-00393604//the National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Rosa/chemistry ; *Oxidative Stress/drug effects ; *Amyloid beta-Peptides/toxicity/metabolism ; Mice ; *Plant Extracts/pharmacology/chemistry ; Male ; Rats ; *Plant Roots/chemistry ; *Oleic Acids/pharmacology/chemistry ; PC12 Cells ; *Neuroprotective Agents/pharmacology/chemistry ; Ethanol/chemistry ; Behavior, Animal/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Antioxidants/pharmacology ; Brain/metabolism/drug effects ; },
abstract = {Researchers have long focused on the accumulation of amyloid beta (Aβ) peptides in the brain as a primary pathological hallmark driving cognitive decline. This study investigated the neuroprotective effects of Rosa rugosa (RR) root extract and its key bioactive constituent, oleamide, against amyloid beta (Aβ)-induced neurotoxicity. Initially, an ethanolic extract of RR root was screened via in vitro assays to assess antioxidant and cytoprotective potential in rat pheochromocytoma cells. Subsequent fractionation, open-column chromatography, and preparatory thin-layer chromatography led to the isolation of oleamide, confirmed by gas chromatography-mass spectrometry and [1]H/[13]C nuclear magnetic resonance analyses. In vivo experiments using intracerebroventricularly injected Aβ in male mice demonstrated that both RR root extract and oleamide significantly improved cognitive performance in the Y-maze and passive avoidance tests. Additionally, oleamide restored acetylcholine levels and reduced malondialdehyde concentrations in brain tissue, indicating mitigation of oxidative stress and support of cholinergic function. No significant toxicity was observed, as evidenced by stable serum transaminase levels and unaltered body or brain weights. These findings highlight oleamide's potential to protect against Aβ-driven pathology through multiple mechanisms, including reduced lipid peroxidation and improved neurotransmission. Further investigations into oleamide's molecular targets and synergy with existing therapies may advance its development as a novel candidate for Alzheimer's disease prevention or adjunct treatment.},
}

Animals
*Rosa/chemistry
*Oxidative Stress/drug effects
*Amyloid beta-Peptides/toxicity/metabolism
Mice
*Plant Extracts/pharmacology/chemistry
Male
Rats
*Plant Roots/chemistry
*Oleic Acids/pharmacology/chemistry
PC12 Cells
*Neuroprotective Agents/pharmacology/chemistry
Ethanol/chemistry
Behavior, Animal/drug effects
Alzheimer Disease/drug therapy/metabolism
Antioxidants/pharmacology
Brain/metabolism/drug effects

@article {pmid40362405,
year = {2025},
author = {Riemann, K and von Ahsen, J and Böhm, T and Schlegel, M and Kreuzer, M and Fenzl, T and Russ, H and Parsons, CG and Rammes, G},
title = {GAL-201 as a Promising Amyloid-β-Targeting Small-Molecule Approach for Alzheimer's Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094167},
pmid = {40362405},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Neuronal Plasticity/drug effects ; Mice ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Microglia/drug effects/metabolism ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Hippocampus/drug effects/metabolism ; Male ; Astrocytes/drug effects/metabolism ; Peptide Fragments/metabolism ; },
abstract = {Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer's disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ1-42, Aβ(p3-42), Aβ1-40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ1-42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the "tgArcSwe" AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Neuronal Plasticity/drug effects
Mice
Disease Models, Animal
*Neuroinflammatory Diseases/drug therapy/metabolism
Microglia/drug effects/metabolism
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
Mice, Transgenic
Hippocampus/drug effects/metabolism
Male
Astrocytes/drug effects/metabolism
Peptide Fragments/metabolism

@article {pmid40362265,
year = {2025},
author = {Zhdanova, DY and Bobkova, NV and Chaplygina, AV and Svirshchevskaya, EV and Poltavtseva, RA and Vodennikova, AA and Chernyshev, VS and Sukhikh, GT},
title = {Effect of Small Extracellular Vesicles Produced by Mesenchymal Stem Cells on 5xFAD Mice Hippocampal Cultures.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094026},
pmid = {40362265},
issn = {1422-0067},
support = {23-13-00035//Russian Science Foundation/ ; },
mesh = {Animals ; *Hippocampus/metabolism/cytology/pathology ; *Mesenchymal Stem Cells/metabolism/cytology ; *Extracellular Vesicles/metabolism ; Mice ; Mice, Transgenic ; *Alzheimer Disease/metabolism/pathology/therapy/genetics ; Humans ; Amyloid beta-Peptides/metabolism ; Neurons/metabolism ; Disease Models, Animal ; Cells, Cultured ; Astrocytes/metabolism ; },
abstract = {Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases leading to impairments in memory, orientation, and behavior. However, significant work is still needed to fully understand the progression of such disease and develop novel therapeutic agents for AD prevention and treatment. Small extracellular vesicles (sEVs) have received attention in recent years due to their potential therapeutic effects on AD. The aim of this study was to determine the potential effect of sEVs in an in vitro model of AD. sEVs were isolated from human Wharton's jelly mesenchymal stem cells (MSCs) by asymmetric depth filtration, a method developed recently by us. AD was modeled in vitro using cells obtained from the hippocampi of newborn 5xFAD transgenic mice carrying mutations involved in familial AD. After isolation, sEVs underwent detailed characterization that included scanning electron microscopy, nanoparticle tracking analysis, confocal microscopy, Western blotting, and Luminex assay. When added to 5xFAD hippocampal cells, sEVs were nontoxic, colocalized with neurons and astrocytes, decreased the level of Aβ peptide, and increased the synaptic density. These results support the possibility that sEVs can improve brain cell function during aging, decrease the risk of AD, and potentially be used for AD therapeutics.},
}

Animals
*Hippocampus/metabolism/cytology/pathology
*Mesenchymal Stem Cells/metabolism/cytology
*Extracellular Vesicles/metabolism
Mice
Mice, Transgenic
*Alzheimer Disease/metabolism/pathology/therapy/genetics
Humans
Amyloid beta-Peptides/metabolism
Neurons/metabolism
Disease Models, Animal
Cells, Cultured
Astrocytes/metabolism

@article {pmid40361641,
year = {2025},
author = {Mafe, AN and Büsselberg, D},
title = {Could a Mediterranean Diet Modulate Alzheimer's Disease Progression? The Role of Gut Microbiota and Metabolite Signatures in Neurodegeneration.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/foods14091559},
pmid = {40361641},
issn = {2304-8158},
support = {NPRP 14S0311-210033//Qatar National Research Fund/ ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), the most common form of dementia, represent a growing global health crisis, yet current treatment strategies remain primarily palliative. Recent studies have shown that neurodegeneration through complex interactions within the gut-brain axis largely depends on the gut microbiota and its metabolites. This review explores the intricate molecular mechanisms linking gut microbiota dysbiosis to cognitive decline, emphasizing the impact of microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites, on neuroinflammation, blood-brain barrier (BBB) integrity, and amyloid-β and tau pathology. The paper highlights major microbiome signatures associated with Alzheimer's disease, detailing their metabolic pathways and inflammatory crosstalk. Dietary interventions have shown promise in modulating gut microbiota composition, potentially mitigating neurodegenerative processes. This review critically examines the influence of dietary patterns, such as the Mediterranean and Western diets, on microbiota-mediated neuroprotection. Bioactive compounds like prebiotics, omega-3 fatty acids, and polyphenols exhibit neuroprotective effects by modulating gut microbiota and reducing neuroinflammation. Furthermore, it discusses emerging microbiome-based therapeutic strategies, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation (FMT), as potential interventions for slowing Alzheimer's progression. Despite these advances, several knowledge gaps remain, including interindividual variability in microbiome responses to dietary interventions and the need for large-scale, longitudinal studies. The study proposes an integrative, precision medicine approach, incorporating microbiome science into Alzheimer's treatment paradigms. Ultimately, cognizance of the gut-brain axis at a mechanistic level could unlock novel therapeutic avenues, offering a non-invasive, diet-based strategy for managing neurodegeneration and improving cognitive health.},
}

@article {pmid40360788,
year = {2025},
author = {Mashhour, MA and Youssef, I and Wahed, MA and Mabrouk, MS},
title = {The Intersection of Genetics and Neuroimaging: A Systematic Review of Imaging Genetics in Neurological Disease for Personalized Treatment.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {2},
pages = {66},
pmid = {40360788},
issn = {1559-1166},
mesh = {Humans ; *Precision Medicine ; *Neuroimaging/methods ; *Nervous System Diseases/genetics/diagnostic imaging/therapy ; Catechol O-Methyltransferase/genetics ; tau Proteins/genetics ; C9orf72 Protein/genetics ; },
abstract = {Imaging genetics is one of the important keys to precision medicine that leads to personalized treatment based on a patient's genetics, phenotype, or psychosocial characteristics. It deepens the understanding of the mechanisms through which genetic variations contribute to neurological and psychiatric disorders. This systematic review overviews the methods and applications of imaging genetics in the context of neurological diseases, mentioning its potential role in personalized medicine. Following PRISMA guidelines, this review systematically analyzes 28 studies integrating genetic and neuroimaging data to explore disease mechanisms and their implications for precision medicine. Selected research included multiple neurological disorders, including frontotemporal dementia, Alzheimer's disease, bipolar disorder, schizophrenia, Parkinson's disease, and others. Voxel-based morphometry was the most common imaging technique, while frequently examined genetic variants included APOE, C9orf72, MAPT, GRN, COMT, and BDNF. Associations between these variants and regional gray matter loss (e.g., frontal, temporal, or subcortical regions) suggest that genetic risk factors play a key role in disease pathophysiology. Integrating genetic and neuroimaging analyses enhances our understanding of disease mechanisms and supports advancements in precision medicine.},
}

Humans
*Precision Medicine
*Neuroimaging/methods
*Nervous System Diseases/genetics/diagnostic imaging/therapy
Catechol O-Methyltransferase/genetics
tau Proteins/genetics
C9orf72 Protein/genetics

@article {pmid40360341,
year = {2025},
author = {Lin, W and Huang, C and Tan, Z and Xu, H and Wei, W and Wang, L},
title = {Cu[II]-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases.},
journal = {Seminars in nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.semnuclmed.2025.03.008},
pmid = {40360341},
issn = {1558-4623},
abstract = {Neurodegenerative diseases, characterized by progressive neuronal degeneration and associated with neuroinflammation and oxidative stress, present significant challenges in diagnosis and treatment. This review explores the potential of copper(II)-bis(thiosemicarbazone) complexes, particularly Cu-ATSM, as a dual-purpose radiopharmaceutical for imaging and therapeutic interventions. Cu-ATSM exhibits unique redox-dependent retention in pathological microenvironments, driven by mitochondrial dysfunction and hyper-reductive states, which enables the noninvasive detection of oxidative stress via positron emission tomography (PET). Preclinical studies demonstrate its efficacy in mitigating neuroinflammation by suppressing glial activation, reducing the secretion of pro-inflammatory cytokines (e.g., TNF-α, MCP-1), and increasing the expression of neuroprotective metallothionein-1 (MT1). Some Clinical research reveals elevated [64]Cu-ATSM uptake in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients, correlating with disease severity and regional oxidative stress markers. Furthermore, Cu-ATSM derivatives show promise in modulating blood-brain barrier (BBB) permeability, enhancing amyloid-β clearance, and restoring copper homeostasis in ALS models. Despite these advances, limitations such as small cohort sizes and heterogeneity in clinical studies underscore the need for larger-scale validation. Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders.},
}

@article {pmid40359691,
year = {2025},
author = {Özdemir, AY and Çetin, EA and Novotný, J and Rudajev, V},
title = {Daidzein effectively mitigates amyloid-β-induced damage in SH-SY5Y neuroblastoma cells and C6 glioma cells.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {187},
number = {},
pages = {118157},
doi = {10.1016/j.biopha.2025.118157},
pmid = {40359691},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is the most debilitating form of dementia, characterized by amyloid-β (Aβ)-related toxic mechanisms such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. The development of AD is influenced by environmental factors linked to lifestyle, including physical and mental inactivity, diet, and smoking, all of which have been associated with the severity of the disease and Aβ-related pathology. In this study, we used differentiated SH-SY5Y neuroblastoma and C6 glioma cells to investigate the neuroprotective and anti-inflammatory effects of daidzein, a naturally occurring isoflavone, in the context of Aβ oligomer-related toxicity. We observed that pre-treatment with daidzein prevented Aβ-induced cell viability loss, increased oxidative stress, and mitochondrial membrane potential decline in both SH-SY5Y and C6 cells. Furthermore, daidzein application reduced elevated levels of MAPK pathway proteins, pro-inflammatory molecules (cyclooxygenase-2 and IL-1β), and pyroptosis markers, including caspase-1 and gasdermin D, all of which were increased by Aβ exposure. These findings strongly suggest that daidzein alleviates inflammation and toxicity caused by Aβ oligomers. Our results indicate that daidzein could be a potential therapeutic agent for AD and other Aβ-related neurodegenerative diseases.},
}

@article {pmid40359673,
year = {2025},
author = {Lee, AL and Hwang, E and Hwang, J},
title = {Exploring the diagnostic potential of EEG theta power and interhemispheric correlation of temporal lobe activities in Alzheimer's Disease through random forest analysis.},
journal = {Computers in biology and medicine},
volume = {192},
number = {Pt B},
pages = {110248},
doi = {10.1016/j.compbiomed.2025.110248},
pmid = {40359673},
issn = {1879-0534},
abstract = {BACKGROUND: Considering the prevalence of Alzheimer's Disease (AD) among the aging population and the limited means of treatment, early detection emerges as a crucial focus area whereas electroencephalography (EEG) provides a promising diagnostic tool. To date, several studies indicated EEG dataset-based models sporting high diagnostic power in distinguishing patients with AD from healthy controls (HC). However, exploration into which features play a crucial role in the diagnosis remains limited.

METHODS: This study investigates the diagnostic capabilities of EEG for distinguishing patients with AD from HCs through random forest classification on EEG features. Band power and cross-correlation from the resting state EEG dataset of 22 HCs and 160 patients with AD were calculated using Welch's periodogram and Pearson's correlation, respectively. Welch's t-test was applied to identify features demonstrating significant differences between patients with AD and HCs. Band power and cross-correlation were analyzed using a random forest classifier (RFC) and feature-importance analysis. The importance of feature categories, defined as subsets of features grouped by frequency bands (for band power features) or brain regions (for cross-correlation features), was quantified by calculating their average occurrence across all hyperparameter configurations.

RESULT: Distinct patterns between the eyes-closed and eyes-open conditions in alpha power were not observed for patients with AD (vs. HC), whereas theta power (4-8 Hz) in all regions was higher in patients with AD (vs. HC)(p<0.05). Interhemispheric cross-correlation in the temporal lobes exhibited the most distinguishable distribution for the cross-correlation dataset. An RFC, exploring 512 models with varied hyperparameters followed by feature-importance analysis based on the mean decrease in impurity, highlighted "theta relative power" and "interhemispheric cross-correlation of channel pairs including temporal channels" as the most important features for distinguishing patients with AD from HCs. RFC on theta-band filtered cross-correlation dataset informed by important features demonstrated the robustness of important features across models with different hyperparameter settings.

DISCUSSION: The models achieved over 97% accuracy and 100% recall in test sets, although the interpretation of this extraordinarily high accuracy warrants caution due to the small dataset size with high data imbalance and the absence of external validation. This methodology demonstrates the efficacy of EEG-based metrics and machine learning in improving our understanding of EEG characteristics in patients with AD, emphasizing the potential of integrating machine learning techniques into clinical practices.},
}

@article {pmid40359180,
year = {2025},
author = {Scalzo, P and Clevenger, C and Cotter, V},
title = {Knowledge, confidence, and behavioral changes after an Alzheimer's disease continuing education program for nurse practitioners.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {},
number = {},
pages = {},
pmid = {40359180},
issn = {2327-6924},
abstract = {Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that currently affects an estimated 6.9 million people in the United States. Despite the growing prevalence of AD, management of this common condition remains suboptimal. To address knowledge and practice gaps related to cognitive evaluation and Alzheimer's diagnosis and treatment, the American Association of Nurse Practitioners (NPs) developed a 1.5-contact hour NP-focused continuing education (CE) program on AD. Changes in learner knowledge, competence, and confidence were assessed with preactivity and postactivity surveys; qualitative follow-up interviews were conducted to evaluate retention of CE material and behavior changes. In total, 4,793 learners (NPs, 93.6%) who completed the activity and self-reported providing patient care were included in the outcomes analysis. In the pre-activity assessment, notable knowledge and competence deficiencies were identified related to the diagnosis, classification, and pharmacotherapeutic management of AD. The CE activity was associated with significant improvements in knowledge and competence, with a 20-percentage point increase in correct response rate from the pre-activity to post-activity survey (p < .001). Learner confidence in their ability to perform key clinical tasks related to Alzheimer's management also improved. Twelve NPs participated in follow-up interviews; most reported that the CE activity reinforced their current practices. Despite improvements in knowledge and competence, certain knowledge gaps persisted, and learners identified several ongoing barriers to optimal management, including lack of access to specialists. Given the changing Alzheimer's landscape, ongoing educational interventions targeted to the NP workforce are needed to serve the growing population of adults at risk for AD.},
}

@article {pmid40359034,
year = {2025},
author = {Chandra, S and Popovic, J and Singhal, NK and Watkins, EA and Dodiya, HB and Weigle, IQ and Salvo, MA and Ramakrishnan, A and Chen, Z and Watson, JT and Shetti, A and Piehl, N and Zhang, X and Cuddy, LK and Sadleir, KR and Schwulst, SJ and Prakriya, M and Gate, D and Sisodia, SS and Vassar, R},
title = {The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI180826},
pmid = {40359034},
issn = {1558-8238},
abstract = {Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.},
}

@article {pmid40359013,
year = {2025},
author = {Singhal, T and Cicero, S and Gale, SA and Horan, N and Dubey, S and Marshall, GA and Weiner, HL},
title = {Dampening of Microglial Activation With Nasal Foralumab Administration in Moderate Alzheimer's Disease Dementia.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000005955},
pmid = {40359013},
issn = {1536-0229},
abstract = {A 78-year-old man with moderate Alzheimer disease (AD) dementia was treated with nasal-foralumab, a fully human anti-CD3 monoclonal antibody, as part of a Food and Drug Administration expanded-access-program, based on previously demonstrated efficacy of anti-CD3 antibody in animal models. 18F-PBR06-PET, utilizing a second-generation 18-kDa-translocator-protein ligand targeting microglia, showed diffuse reduction of radiotracer uptake throughout the brain, following 3 months of nasal-foralumab compared with baseline. In particular, precuneus, posterior cingulate and anterior cingulate gyri, regions that had high levels of amyloid deposition on a baseline 18F-Florbetapir-PET scan, showed reduction in microglial activation after nasal-foralumab treatment for 3 months.},
}

@article {pmid40357876,
year = {2025},
author = {Yang, Z and Liu, T and Kong, X and Wei, J},
title = {Neuroprotective Effect of Abscisic Acid on MPTP-Induced Parkinson's Disease in Mice.},
journal = {Molecular nutrition & food research},
volume = {},
number = {},
pages = {e70111},
doi = {10.1002/mnfr.70111},
pmid = {40357876},
issn = {1613-4133},
support = {32161143021 81271410//National Natural Science Foundation of China/ ; 182300410313//Henan Natural Science Foundation of China/ ; CJ1205A0240018//Bio-Med Interdisciplinary Innovative Program of Henan University/ ; },
abstract = {Parkinson's disease (PD) is the second largest neurodegenerative disease after Alzheimer's disease (AD), and neuroinflammation is one of its important causes. So far, there is no clear evidence that drugs can improve the onset of PD, so it is crucial to find and develop effective drugs for PD treatment. Abscisic acid (ABA) is a phytohormone with structural and medicinal functions similar to the PPAR-γ agonist thiazolidinedione drugs (TZDs). It has played therapeutic effects in a variety of inflammatory diseases, but the role and mechanism of PD have not been defined. The present study aimed to gain insight into the neuroprotection effects and mechanism of ABA in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD models. In this study, we observed that in addition to significant behavioral abnormalities in MPTP-induced mice, Inflammatory parameters such as ion calcium-binding adaptor molecule 1 (IBA-1), glial fibrillary acid protein (GFAP), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were also significantly increased in substantia nigra pars compacta (SNpc). ABA treatment restored behavioral abnormalities and significantly reduced these inflammatory parameters in MPTP-induced mice. Interestingly, these effects were not related to the activation of the lanthionine synthetase C-like protein 2 (LANCL2) but were related to the regulation of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Intraperitoneal injection of ABA ameliorated the MPTP-induced increase in PPAR-γ and peroxisome proliferator-activated receptor co-activator-1α (PGC-1α) expression. Our findings suggest that intraperitoneal injection of ABA is neuroprotective against neurodegeneration induced by MPTP, and this effect is associated with the downregulation of neuroinflammation and modulation of the expression of PPAR-γ and PGC-1α. These results suggest that ABA is expected to develop as a therapeutic candidate for PD.},
}

@article {pmid40357771,
year = {2025},
author = {Deng, Y and Chen, C and Li, H and Wang, T and Zhang, X and Wang, X and Pan, G},
title = {Traditional Chinese Medicines for Alzheimer's Disease: Current Knowledge, Clinical Applications, and Future Directions.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266347052250407110353},
pmid = {40357771},
issn = {1873-4294},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a significant challenge to the health of the global aging population. Despite extensive research, the complex mechanisms underlying AD pathogenesis remain largely elusive. In recent years, a growing number of clinical studies have demonstrated the preventive and therapeutic potential of Traditional Chinese Medicine (TCM) against AD through multiple pathways, targets, and compounds. In this study, we conducted a review of the literature published over the past 20 years through international and domestic databases, including PubMed, Medline, Cochrane Library, CNKI, SinoMed, Wanfang, and VIP Journal Integration Platform. This review systematically evaluates current research advancements regarding single-herb preparations, bioactive constituents, and compound formulations in Traditional Chinese Medicine (TCM), with focused analysis on three therapeutic categories: tonifying herbs, blood-activating and stasis-eliminating agents, as well as orifice-opening, phlegm-resolving, and mind-stabilizing medicinal substances. Furthermore, this review discusses the potential mechanisms underpinning the anti-AD effects of TCMs. By integrating these insights, this review aims to establish a theoretical foundation for the application of TCMs in AD treatment and provide a reference for future pharmacological studies and the development of health-related products.},
}

@article {pmid40357255,
year = {2025},
author = {Li, YQ and Chen, ZW and He, H and Liu, YW and Ye, F and Yang, ZQ and Li, DH and Bao, QN and Zhang, XY and Zhong, WQ and Wu, KX and Yao, J and Xu, P and Yang, SQ and Wang, ZW and Yin, ZH and Liang, FR},
title = {Acupuncture Modulates Spatiotemporal Neuronal Dynamics in Mild Cognitive Impairment: A Protocol for Simultaneous EEG-fMRI Study.},
journal = {Journal of multidisciplinary healthcare},
volume = {18},
number = {},
pages = {2523-2539},
pmid = {40357255},
issn = {1178-2390},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is characterized by abnormal changes in spatiotemporal neuronal specificity responses. Simultaneous electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) offers a novel approach to measure these changes. Emerging evidence suggests that acupuncture may enhance cognitive function by modulating spatial or temporal central activity in individuals with MCI. However, no studies have investigated the detailed mechanisms underlying this effect.

METHODS: This randomized controlled neuroimaging trial will enroll 60 patients with MCI, who will be randomly assigned to one of two groups: a real acupuncture (RA) group or a sham acupuncture (SA) group. The trial period will last 12 weeks, during which participants will receive 24 sessions of acupuncture twice weekly. The primary outcome measure will be the improvement in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score from baseline to post-treatment. Secondary outcomes will include improvements in specific cognitive domains such as memory, executive function, language, and attention. Simultaneous EEG-fMRI combined with correlation analysis, regression analysis, and joint independent component analysis (jICA) will elucidate the spatiotemporal central modulatory mechanisms of acupuncture in MCI patients.

DISCUSSION: This study may reveal that real acupuncture can treat cognitive impairment by modulating the brain's spatiotemporal neuronal specificity activity. Our findings will provide scientific evidence for the efficacy of acupuncture in the treatment of MCI and further add to the understanding of the neural mechanisms.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier [ChiCTR2400084666].},
}

@article {pmid40357234,
year = {2025},
author = {Wang, T and Liu, Y and Lu, Y and Chi, L},
title = {NTN-1 attenuates amyloid-β-mediated microglial neuroinflammation and memory impairment via the NF-κB pathway and NLRP3 inflammasome in a rat model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1516399},
pmid = {40357234},
issn = {1663-4365},
abstract = {INTRODUCTION: Neuroinflammation driven by microglial activation represents a pivotal pathological mechanism underlying brain injury in Alzheimer's disease (AD), with NLRP3 inflammasome activation being a hallmark feature of this process. Netrin-1 (NTN-1) was recently shown to have potent anti-inflammatory and anti-apoptotic properties in a range of inflammatory diseases; however, its potential effect on neuroinflammation in AD treatment has not been well examined. Accordingly, this study aimed to investigate the effects of NTN-1 on cognitive impairment and to explore the anti-inflammatory properties related to the NLRP3 inflammasome and NF-κB signaling in Aβ1-42-induced rat models.

METHODS: We assessed the effects of NTN-1 on neurobehavioral function, microglial activation and neuroinflammation mechanisms in Aβ1-42-treated rats using the Morris water maze test and Western blotting.

RESULTS: Our results indicated that microinjections of NTN-1 attenuated Aβ1-42-induced memory and cognitive dysfunction and significantly inhibited microglial proliferation and NLRP3 inflammasome activation in the hippocampus and cortex of AD rats. Additionally, NTN-1 effectively prevented proinflammatory factor (IL1β and IL18) release and NF-κB signaling upstream activation.

DISCUSSION: Overall, the results of the present study indicated that exogenous NTN-1 treatment prevented neuroinflammation and cognitive deficits by inhibiting microglial activation, which is possibly mediated by the NF-κB signaling pathway and NLRP3 inflammasome activation in Aβ1-42-simulated rat models. NTN-1 emerges as a promising therapeutic candidate for mitigating microglia-mediated neuropathology in AD through its anti-inflammatory properties.},
}

@article {pmid40357142,
year = {2025},
author = {Karneboge, J and von Boehn, F and Haberstroh, J},
title = {Standardization of criteria in MacCAT-T and MacCAT-CR for monoclonal anti-beta-amyloid antibodies: A Delphi study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {2},
pages = {e70112},
doi = {10.1002/dad2.70112},
pmid = {40357142},
issn = {2352-8729},
abstract = {INTRODUCTION: Assessing capacity to consent to treatment and participation in clinical research with monoclonal anti-beta-amyloid antibodies is critical, especially given the frequent uncertainty in the eligible population. Capacity tends to be underestimated in Alzheimer's patients and overestimated in those with mild cognitive impairment (MCI).

METHODS: Using the Delphi method, an international expert panel (N = 21) was surveyed in two waves.

RESULTS: The participants reached consensus on 85 % of identified features, 90 % of benefits, and 88 % of risks.

DISCUSSION: The resulting standard emphasizes the understanding subscale of the MacArthur competence assessment tools (MacCAT) for both treatment and research, supporting use across clinical and research settings. Despite proven utility, only 4 % of psychiatrists currently use tools like MacArthur Competence Assessment Tool for Treatment (MacCAT-T). This consensus aims to promote wider adoption of capacity assessments, integrating them routinely into clinical practice to balance patient autonomy with beneficence.},
}

@article {pmid40356905,
year = {2025},
author = {Saggu, S and Pless, A and Dew, E and Ware, D and Jiao, K and Wang, Q},
title = {Monoamine signaling and neuroinflammation: mechanistic connections and implications for neuropsychiatric disorders.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1543730},
doi = {10.3389/fimmu.2025.1543730},
pmid = {40356905},
issn = {1664-3224},
mesh = {Humans ; *Signal Transduction ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology ; *Biogenic Monoamines/metabolism ; *Mental Disorders/metabolism ; Cytokines/metabolism ; },
abstract = {Monoamines, including norepinephrine, serotonin, and dopamine, orchestrate a broad spectrum of neurophysiological and homeostatic events. Recent research shows a pivotal role for monoaminergic signaling in modulating neuroinflammation by regulating proinflammatory cytokines and chemokines within the central nervous system. Importantly, this modulation is not unidirectional; released proinflammatory cytokines markedly "feedback" to influence the metabolism of monoamine neurotransmitters, impacting their synthesis, release, and reuptake. This bidirectional interplay significantly links monoaminergic pathways and neuroinflammatory responses. In this review, we summarize current knowledge of the dynamic interactions between monoamine signaling and neuroinflammation, as well as their critical implications for the pathophysiology of neuropsychiatric disorders, including Parkinson's Disease, Major Depressive Disorder, and Alzheimer's Disease. By integrating recent findings, we shed light on potential therapeutic targets within these interconnected pathways, providing insights into novel treatment strategies for these devastating disorders.},
}

Humans
*Signal Transduction
Animals
*Neuroinflammatory Diseases/metabolism/immunology
*Biogenic Monoamines/metabolism
*Mental Disorders/metabolism
Cytokines/metabolism

@article {pmid40356629,
year = {2025},
author = {Liu, W and Zhao, Y and Rao, Y and Wu, Z and Peng, Y and Gong, L},
title = {Frontiers and hotspot evolution in research on Alzheimer's disease and hypertension: a bibliometric analysis from 2004 to 2023.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1514054},
doi = {10.3389/fneur.2025.1514054},
pmid = {40356629},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that imposes a heavy burden on patients and their families. Hypertension is an important risk factor for AD, but the specific mechanism of its impact is still unclear. This study thus aimed to analyze the relationship and trend changes between AD and hypertension through bibliometric methods.

METHODS: Literature on AD and hypertension was retrieved from the Web of Science Core Collection (WoSCC) database between 2004 and 2023. Data regarding countries, institutions, authors and journals were sourced from WoSCC. CiteSpace and VOSviewer were used for data visualization, including author collaboration, timelines view of references, reference bursts and overlay visualization maps of keywords. Excel 2018 software was used for the statistical analysis.

RESULTS: A total of 1,833 publications were ultimately included. From 2004 to 2023, the number of publications per year basically showed an increasing trend. The United States (United States) not only had the largest output of publications and the highest H-index but also had the seven highest frequencies of publication institutions. Kehoe, Patrick ranked first with the most articles among 9,330 authors. The journal with the most published articles was the Journal of Alzheimer's Disease. Reference analysis revealed a hotspot in the exploration of the pathophysiological association between AD and hypertension. Second, the treatment effects and potential risks of antihypertensive drugs (AHDs) on AD are also the focus of research. Researchers have carried out a series of studies ranging from basic research to clinical research on AHDs for the treatment of AD. Finally, personalized treatment strategies will also become one of the hotspots of future research. Controlling hypertension through lifestyle changes and medication interventions in AD patients is a promising strategy. The analysis of keywords revealed that "amyloid deposition," "preeclampsia," "Corona Virus Disease 2019 (COVID-19)" and "biomarkers" have been research hotspots in recent years.

CONCLUSION: By analyzing the references and keywords, we summarized the hot topics and research trends in this field. These findings provide useful information for researchers to explore the relationship between hypertension and AD further, with the hope of providing more effective treatments for AD patients to delay disease progression and improve quality of life.},
}

@article {pmid40356042,
year = {2025},
author = {Gay, MD and Baldaranov, D and Donohue, MC and Jack, CR and Sperling, RA and Aisen, PS and Rafii, MS},
title = {Relationship between use of anti-platelet agents, oral anti-coagulants, and Aβ burden with cerebral microhemorrhages in cognitively asymptomatic adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70167},
doi = {10.1002/alz.70167},
pmid = {40356042},
issn = {1552-5279},
support = {U19AG010483//National Institutes of Health National Institute on Aging/ ; R01AG063689//National Institutes of Health National Institute on Aging/ ; U24AG057437//National Institutes of Health National Institute on Aging/ ; //An anonymous foundation/ ; //David and Lucile Packard Foundation/ ; //Foundation for the National Institutes of Health/ ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; },
mesh = {Humans ; Male ; Female ; *Amyloid beta-Peptides/metabolism ; *Cerebral Hemorrhage/epidemiology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; *Platelet Aggregation Inhibitors/therapeutic use/adverse effects ; *Anticoagulants/adverse effects/therapeutic use ; Apolipoprotein E4/genetics ; Prevalence ; Middle Aged ; *Alzheimer Disease ; Risk Factors ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Cerebral microhemorrhages (CMHs) are detectable by magnetic resonance imaging (MRI). CMHs in deep brain regions are linked to hypertensive vasculopathy, while those in lobar regions with amyloid beta (Aβ) deposition in blood vessels. This study aims to determine the association between anti-thrombotic treatment and CMH prevalence among cognitively asymptomatic adults, and to assess the role of Aβ markers, apolipoprotein E (APOE) ε4 carrier status, and cardiovascular risk factors in CMH development.

METHODS: Using baseline data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, we examined CMH presence via 3T MRI, along with medication use, APOE ε4 carrier status, medical history, and blood pressure.

RESULTS: Our analysis showed a significantly higher prevalence of CMHs in the A4 cohort (17.3%) compared to the LEARN cohort (2.6%).

DISCUSSION: Factors such as male sex, age, Aβ markers, and APOE ε4 status were significantly associated with higher CMH prevalence in the A4 cohort. However, anti-thrombotic treatment did not show association with overall CMHs.

HIGHLIGHTS: Male sex, age > 75, amyloid beta (Aβ) burden, and apolipoprotein E (APOE) ε4 homozygosity are significantly associated with higher prevalence of CMHs (cerebral microhemorrhages) in a cohort of cognitively asymptomatic individuals. Male sex, age > 75, Aβ burden, and APOE ε4 homozygosity are significantly associated with higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals. Anti-platelet or anti-coagulant usage were not associated with an increased prevalence of CMHs in either brain location or overall, in a cohort of cognitively asymptomatic individuals. History of a lipid disorder is associated with a higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals.},
}

Humans
Male
Female
*Amyloid beta-Peptides/metabolism
*Cerebral Hemorrhage/epidemiology/diagnostic imaging
Aged
Magnetic Resonance Imaging
*Platelet Aggregation Inhibitors/therapeutic use/adverse effects
*Anticoagulants/adverse effects/therapeutic use
Apolipoprotein E4/genetics
Prevalence
Middle Aged
*Alzheimer Disease
Risk Factors
Aged, 80 and over

@article {pmid40355993,
year = {2025},
author = {Yu, J and Zhu, L and Song, Y and Shi, B and Zhou, X},
title = {Positive Impact of Holistic Nursing on Cognitive Impairment and Psychiatric Symptoms in Patients With Alzheimer's Disease.},
journal = {Actas espanolas de psiquiatria},
volume = {53},
number = {3},
pages = {586-597},
doi = {10.62641/aep.v53i3.1948},
pmid = {40355993},
issn = {1578-2735},
mesh = {Humans ; *Alzheimer Disease/nursing/psychology/complications ; Female ; Male ; Aged ; Prospective Studies ; *Cognitive Dysfunction/nursing/therapy/etiology ; *Holistic Nursing/methods ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) affects millions of elderly individuals worldwide and has been clinically recognized as one of the most significant disorders compromising quality of life in late-stage human development. The objective of this study is to systematically evaluate the influence of holistic nursing (HN) on patients with AD, thereby providing evidence-based references for clinical practice.

METHODS: A total of 105 patients with AD hospitalized in our hospital between January 2023 and January 2024 were enrolled for prospective analysis. Among them, 58 received conventional care (control group), and 47 received HN (observation group). Before and following the nursing interventions, both groups underwent assessment using the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Montreal Cognitive Assessment (MoCA), and Self-rating Anxiety/Depression Scales (SAS/SDS). In addition, neurotransmitter levels and neuroinflammatory markers were measured using enzyme-linked immunosorbent assay and fully automated chemiluminescent immunoassay. Treatment compliance, incidence of adverse events, and family satisfaction were also recorded and compared between the two groups.

RESULTS: After nursing interventions, the observation group demonstrated significantly higher MMSE and MoCA scores compared to the control group. Conversely, NPI, ADAS-cog, SAS, and SDS scores were notably lower in the observation group (p < 0.05). Furthermore, neurotransmitter levels were significantly elevated in the observation group, while the concentrations of central nervous system-specific protein β (S100β) and interleukin-1β (IL-1β) were significantly reduced (p < 0.05). Although the incidence of adverse events did not differ significantly between the two groups (p > 0.05), the observation group exhibited higher treatment compliance and greater family satisfaction (p < 0.05).

CONCLUSION: HN effectively improves cognitive function and alleviates psychiatric symptoms in AD patients, supporting its recommendation for clinical application.

CLINICAL TRIAL REGISTRATION: No. NCT06868004.},
}

Humans
*Alzheimer Disease/nursing/psychology/complications
Female
Male
Aged
Prospective Studies
*Cognitive Dysfunction/nursing/therapy/etiology
*Holistic Nursing/methods
Aged, 80 and over

@article {pmid40355750,
year = {2025},
author = {Rosenbloom, M and Schnee, A and Nimma, S and Lutz, H and Gzesh, D and Weisman, D},
title = {Monoclonal antibody administration in an academic institution and private neurological practice: a tale of two clinics.},
journal = {Journal of neurology},
volume = {272},
number = {6},
pages = {394},
pmid = {40355750},
issn = {1432-1459},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/drug therapy/economics ; *Private Practice/economics ; *Academic Medical Centers/economics ; *Antibodies, Monoclonal/therapeutic use/economics ; *Neurology ; Middle Aged ; Aged, 80 and over ; },
abstract = {The emergence of monoclonal antibody (MABs) drugs since the FDA approval of lecanemab has resulted in dramatic changes in the clinical approach and management of early-stage Alzheimer's disease (AD). Challenges with MAB adoption into clinical practice may vary depending on whether the institution is an academic/integrated healthcare organization versus a private neurological practice. We have combined demographic and clinical data from a high-volume East coast private neurology practice and a West coast academic memory clinic at post-MAB adoption. Combined data of N = 165 patient showed the following demographics: mean age 72, 67% female, 92% Caucasian, average MOCA 18/30 with amyloid status confirmed by CSF in 72% of patients. Overall, ARIA rates were 8% for ARIA-E and 7% for ARIA-H, and there were no mortalities over the observation period. Three patients required immediate medical attention due to ARIA radiographic findings associated with clinical symptoms. The private practice enrolled patients with lower average cognitive screening scores than the academic practice, but was more efficient at initiation therapy (mean # of weeks between diagnosis and treatment 97 versus 149 days). The average patient out-of-pocket cost was ($654.38) significantly less than the 20% of the annual drug cost as previously estimated. The findings from two separate clinical environments support the notion that ARIA risk associated with lecanemab is no greater than what was found in the CLARITY-AD trial and that the costs to the patient were less than predicted. This study was limited by the lack of 12 month efficacy data. Additional real-world data relating to the clinical effectiveness of MAB use in clinical practice will be necessary to best determine the risk/benefit ratio of these drugs in community populations.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/drug therapy/economics
*Private Practice/economics
*Academic Medical Centers/economics
*Antibodies, Monoclonal/therapeutic use/economics
*Neurology
Middle Aged
Aged, 80 and over

@article {pmid40354064,
year = {2025},
author = {Paczynski, M and Hofmann, A and Posey, Z and Gregersen, M and Rudman, M and Ellington, D and Aldinger, M and Musiek, ES and Holtzman, DM and Bateman, RJ and Long, JM and Ghoshal, N and Carr, DB and Dow, A and Namazie-Kummer, S and Jana, N and Xiong, C and Morris, JC and Benzinger, TLS and Schindler, SE and Snider, BJ},
title = {Lecanemab Treatment in a Specialty Memory Clinic.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.1232},
pmid = {40354064},
issn = {2168-6157},
abstract = {IMPORTANCE: Two monoclonal antibodies targeting amyloid plaques, lecanemab and donanemab, have received traditional US Food and Drug Administration (FDA) approval for the treatment of early symptomatic Alzheimer disease (AD). The most significant adverse events associated with these therapies are infusion-related reactions and amyloid-related imaging abnormalities (ARIA) with edema/effusion (ARIA-E) and/or hemorrhage/hemosiderin deposition (ARIA-H). The feasibility and safety of providing these treatments in clinical practice is unclear.

OBJECTIVE: To examine the feasibility and safety of treating patients in specialty memory clinics with lecanemab.

This retrospective analysis of consecutive patients in whom lecanemab was initiated between August 1, 2023, and October 1, 2024, at Washington University Memory Diagnostic Center, an outpatient specialty memory clinic. Lecanemab was initiated in 234 patients with early symptomatic AD. Eligibility was based on the FDA label and appropriate use recommendations with occasional exceptions.

EXPOSURE: Patients were treated with lecanemab, 10 mg/kg, intravenously every 2 weeks.

MAIN OUTCOMES AND MEASURES: Infusion-related reactions, ARIA, and withdrawal from treatment were assessed.

RESULTS: The 234 patients treated with lecanemab had a mean age of 74.4 (SD, 6.7) years, 117 were female (50%), and 117 were male. (50%) Infusion-related reactions occurred in 87 patients (37%) and were typically mild. Of the 194 patients at risk for ARIA during the study period, 44 had at least 1 microhemorrhage and/or superficial siderosis before initiation of lecanemab (23%). Over an average treatment period of 6.5 months, 42 total patients (22%) developed ARIA; 29 developed ARIA-E with or without ARIA-H (15%) and 13 developed isolated ARIA-H (6.7%). Eleven patients (5.7%) developed symptomatic ARIA, 2 of those patients (1.0%) with clinically severe symptoms. No patients developed a macrohemorrhage or died. Patients with mild dementia had a 27% rate of symptomatic ARIA; those with mild cognitive impairment or very mild dementia had a 1.8% rate. Overall, 23 of 234 patients (9.8%) withdrew from treatment for various reasons, 10 for ARIA (4.3%).

CONCLUSIONS AND RELEVANCE: A single-specialty memory clinic initiated lecanemab treatment in 234 patients over 14 months. The frequency of significant adverse events, including ARIA, was manageable. These results may inform discussions about the risks of anti-amyloid treatments.},
}

@article {pmid40353816,
year = {2025},
author = {Wang, JL and Dong, YY and Liu, PL and Liao, XR and Qi, LJ and Huang, QY and Liu, H},
title = {Dual-Targeting Protein-Based Delivery System for Enhanced Drug Therapy of Neurodegenerative Disorders.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.5c00267},
pmid = {40353816},
issn = {2576-6422},
abstract = {Conventional drugs for Alzheimer's disease (AD) treatment often suffer from low bioavailability due to the blood-brain barrier (BBB). In this investigation, we developed a dual-brain targeting protein-based drug delivery system for nose-to-brain drug delivery. The dual-brain targeting drug delivery system, Donepezil@Tf/cRGD-CS, was prepared using a simple self-assembly method. Donepezil was encapsulated in transferrin (Tf) nanoparticles, which were decorated with cRGD-conjugated chitosan (cRGD-CS), enabling dual-targeted drug delivery. Due to the specific interactions between Tf and the transferrin receptor (TfR) as well as cRGD and integrins, Donepezil@Tf/cRGD-CS exhibited enhanced BBB penetration as well as improved cellular uptake by brain neurons. An in vitro BBB model confirmed the enhanced permeability of the dual-targeted drug-loaded nanoparticles across the BBB. Compared to free donepezil, Donepezil@Tf/cRGD-CS nanoparticles significantly improved therapeutic outcomes, including reduced neurotoxicity induced by Aβ25-35 and downregulation of apoptosis-related proteins and Tau proteins. This study offers an effective strategy for improving the therapeutic outcomes of central nervous system diseases.},
}

@article {pmid40353733,
year = {2025},
author = {Kim, JH and Seo, HJ and Noh, BW and He, MT and Choi, YH and Cho, EJ and Noh, JS},
title = {Protective effects of Cuscuta chinensis Lam. extract against learning and memory dysfunction induced by streptozotocin and amyloid β25-35 in vivo model.},
journal = {Archives of physiology and biochemistry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13813455.2025.2502861},
pmid = {40353733},
issn = {1744-4160},
abstract = {Alzheimer's disease (AD) is associated with hyperglycaemia and amyloid beta (Aβ) accumulation. In the present study, we investigated whether an aqueous extract of Cuscuta chinensis Lam. (CCWE) improved cognitive disorder in a hyperglycaemic and cognitive-impaired mouse model. Hyperglycaemia was induced by streptozotocin (STZ, 50 mg/kg) and a single intracerebroventricular injection of Aβ25-35 (25 nM) was performed. The Aβ25-35-injected hyperglycaemic mice were then administered CCWE (100 or 200 mg/kg/day) for 14-d. The protective effects of the CCWE were evaluated by behavioural tests and western blot analysis. The bioactive compounds in CCWE were isolated by UPLC-QTOF/MS analysis. The administration of CCWE improved the learning and memory function in STZ/Aβ25-35-injected mice. Moreover, CCWE positively regulated the amyloidogenic pathway-related proteins and insulin signalling-related proteins. The bioactive components in CCWE were also identified. These findings suggest the possibility of CCWE as a potential candidate for the dual-targeting treatment of hyperglycaemia and AD.},
}

@article {pmid40353519,
year = {2025},
author = {Shahid, MM and Hohman, G and Eldeeb, M},
title = {Fine-Tuning Ferroptosis by Modulating GPX4 and Its Potential in Mitigating Neuronal Degeneration in Parkinson's Disease.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {26},
number = {9},
pages = {e202401052},
doi = {10.1002/cbic.202401052},
pmid = {40353519},
issn = {1439-7633},
mesh = {*Ferroptosis/drug effects ; *Parkinson Disease/metabolism/pathology/drug therapy ; Humans ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Animals ; },
abstract = {The increasing prevalence of neurodegenerative diseases necessitates the development of novel approaches to study, diagnose, and treat these devastating disorders. Accordingly, there is a critical need to precisely address the gap in the biochemical and physiological mechanisms that underlie neurodegenerative diseases to promote advancements in therapeutic interventions. Parkinson's Disease (PD), the second most common neurodegenerative disorder after Alzheimer's, demands further research focused on unravelling the rather intricate molecular mechanisms that drive its progression upon different cell signaling cues. While alpha-synuclein aggregation and mitochondrial dysfunction are two cellular hallmarks of the molecular pathophysiology of PD, few drugs are currently in clinical trials for treatment of PD, which warrants further studies to identify new therapeutic molecular targets. Herein, we briefly highlight some of the reported roles of ferroptosis, a modality of cell death that is driven by iron-dependent phospholipid peroxidation, and its regulation by glutathione peroxidase 4 (GPX4). We discuss the interconnectedness between lipid peroxidation and GPX4 regulation in the context of molecular pathogenesis of PD. Future studies are imperative in investigating the physiological role of ferroptosis and the translational impact of ferroptosis-specific modulators in studying PD biology.},
}

*Ferroptosis/drug effects
*Parkinson Disease/metabolism/pathology/drug therapy
Humans
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Lipid Peroxidation/drug effects
Animals

@article {pmid40353063,
year = {2025},
author = {Ma, YN and Hu, X and Karako, K and Song, P and Tang, W and Xia, Y},
title = {The potential and challenges of TREM2-targeted therapy in Alzheimer's disease: insights from the INVOKE-2 study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1576020},
doi = {10.3389/fnagi.2025.1576020},
pmid = {40353063},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder with a growing global burden. With the rising incidence of AD, the need for novel therapeutic targets has become increasingly critical. TREM2, a receptor expressed on microglial cells, plays a crucial role in modulating neuroinflammation and clearing pathological substrates, making it a promising candidate for AD therapy. However, the recent clinical trial INVOKE-2 failed to demonstrate significant clinical benefits of the TREM2-targeted antibody AL002, raising doubts about the efficacy of TREM2-targeted methods. This article examines the role of TREM2 in AD pathogenesis, evaluates potential reasons for the disappointing outcomes of the INVOKE-2 trial, and discusses future directions for TREM2-based therapies. Factors such as treatment timing, dosage optimization, patient genetic variability, and combination therapy strategies are identified as critical determinants of therapeutic success. Future studies should aim to refine treatment strategies, identify precise indications, and explore the potential for combination therapies to enhance efficacy.},
}

@article {pmid40351705,
year = {2025},
author = {Sun, C and Sha, S and Shan, Y and Gao, X and Li, L and Xing, C and Guo, Z and Du, H},
title = {Intranasal Delivery of BACE1 siRNA and Berberine via Engineered Stem Cell Exosomes for the Treatment of Alzheimer's Disease.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {5873-5891},
pmid = {40351705},
issn = {1178-2013},
mesh = {*Alzheimer Disease/therapy/drug therapy/genetics ; Animals ; *Exosomes/chemistry ; *Amyloid Precursor Protein Secretases/genetics ; *Aspartic Acid Endopeptidases/genetics ; Administration, Intranasal ; Humans ; Mice ; *RNA, Small Interfering/administration & dosage/genetics ; *Berberine/administration & dosage/pharmacology ; Disease Models, Animal ; Mesenchymal Stem Cells/cytology ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a common progressive and irreversible neurodegenerative disease. AD accounts for 60%-70% of all dementia cases, ranking as the seventh leading cause of death globally. Human umbilical cord mesenchymal stem cells (hUC-MSCs) characterized by their abundant availability and low immunogenicity, have demonstrated significant therapeutic potential for AD in both preclinical studies and clinical trials. The use of exosomes can help mitigate the issues associated with cellular therapies. However, the clinical application of hUC-MSCs remains challenging due to their inability to effectively traverse the blood-brain barrier (BBB) and reach pathological sites. Therapeutic strategies utilizing exosomes derived from hUC-MSCs (Exos) have emerged as an effective approach for AD intervention.

METHODS: Here, we used ultrasound to construct multifunctional Exos (MsEVB@R/siRNA) for AD therapy. We obtained small interfering RNA for β-site precursor protein lyase-1 (BACE1 siRNA) and berberine for co-delivery into the brain. Berberine, a classical anti-inflammatory agent, effectively alleviates neuroinflammation in AD pathogenesis. BACE1 serves as the pivotal cleavage enzyme in amyloid β-protein (Aβ) formation, where silencing BACE1 synthesis through BACE1 siRNA significantly reduces Aβ production. In a 5xFAD mouse model, Exos selectively targeted microglial and neuronal cells after nasal delivery under the action of neural cell-targeting peptide rabies virus glycoprotein 29 (RVG29).

RESULTS: BACE1 siRNA and berberine (BBR) loading enhanced the effectiveness of Exos in improving cognitive function, promoting nerve repair and regeneration, reducing inflammatory cytokine expression, and suppressing glial responses. BACE1 siRNA release was confirmed to reduce BACE1 expression and Aβ deposition. Concurrently, berberine effectively suppressed the release of inflammatory factors, thereby reducing neuroinflammation.

CONCLUSION: In conclusion, the nasal delivery of engineered exosomes is a potentially effective method for treating AD.},
}

*Alzheimer Disease/therapy/drug therapy/genetics
Animals
*Exosomes/chemistry
*Amyloid Precursor Protein Secretases/genetics
*Aspartic Acid Endopeptidases/genetics
Administration, Intranasal
Humans
Mice
*RNA, Small Interfering/administration & dosage/genetics
*Berberine/administration & dosage/pharmacology
Disease Models, Animal
Mesenchymal Stem Cells/cytology
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Brain/metabolism

@article {pmid40351431,
year = {2025},
author = {Bai, JM and Li, T and Di, X and Yang, JX and Cui, ZQ and Min, DY and Shen, YF and Shan, SY and Zhang, YX and Shi, YJ and Xu, ZL and Dou, DQ and Xiao, HH},
title = {The active metabolite of Epimedii Folium promotes hippocampal neurogenesis in APP/PS1 mice by alleviating mitochondrial dysfunction.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1546256},
pmid = {40351431},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD), the most common form of dementia, currently has no effective cure. Epimedii Folium (EF), a traditional Chinese medicine known as Yin-yang-huo, has demonstrated significant neuroprotective properties.

METHODS: In this study, neural stem cells overexpressing the APPswe gene (APP-NSCs) were used as an in vitro AD model. The CCK-8, LDH, neurosphere formation, and BrdU incorporation assays were employed to identify the most effective bioactive metabolite of EF in promoting NSC proliferation. Subsequently, JC-1 staining, ATP quantification, and ROS assays were conducted to evaluate the protective effects of Icariside II (ICS II)-identified as the most effective metabolite-on mitochondrial function. APP/PS1 transgenic mice received an oral administration of 10 mg/kg ICS II for 7 weeks. Cognitive function was assessed using the Morris water maze and nest-building tests, while H&E and Nissl staining were used to evaluate brain tissue pathology. Transmission electron microscopy (TEM) examined the ultrastructural integrity of hippocampal neurons, immunofluorescence assessed hippocampal neurogenesis, and Western blotting quantified proteins involved in mitochondrial dynamics. Additionally, Rotenone (Rot), a mitochondrial respiratory chain inhibitor, was applied to disrupt mitochondrial function, allowing an evaluation of whether the neurogenesis-promoting effect of ICS II depends on maintaining mitochondrial structure and function.

RESULTS AND DISCUSSION: The results demonstrated that ICS II exhibited the strongest capacity to promote APP-NSC proliferation (P < 0.01, η[2] = 0.845), followed by Icariin and Icaritin. ICS II treatment significantly ameliorated cognitive deficits (P < 0.01, η[2] = 0.883), neuronal damage, and impairments in neurogenesis in adult APP/PS1 mice. Moreover, ICS II rescued mitochondrial damage by upregulating fusion proteins (Mfn1 and Mfn2) and downregulating fission proteins (p-Drp1/Drp1 and Mff); however, these protective effects were negated by Rot administration. In conclusion, this study identifies ICS II as one of the most effective metabolites of EF, promoting hippocampal neurogenesis and alleviating mitochondrial dysfunction in APP/PS1 mice, thereby offering promising therapeutic potential for AD.},
}

@article {pmid40351411,
year = {2025},
author = {Mana, L and Chen, F and Yuan, X},
title = {KaiXinSan-JiaWei ameliorates cognitive dysfunction in APP/PS1 mice by intervening in gut microbiota and its metabolites.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1483883},
pmid = {40351411},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory loss. Chinese medicine's therapeutic effect on AD has become a promising treatment option in recent years, and the Chinese herbal compound Kai Xin San-Jia Wei (KXSJW) is one of its representatives. This study employed a comprehensive approach, including 16S rRNA and Gaschromatography-mass spectrometry (GC-MS) analysis, to investigate the therapeutic efficacy and intrinsic mechanism of KXSJW on AD.

METHODS: 50 3-month-old APP[swe]/PS1[dE9] transgenic mice were randomly divided into 5 groups (n = 10): model group (M), donepezil group (Don), KXSJW-low dose group (KJW-L), KXSJW- medium dose group (KJW-M), KXSJW-high dose group (KJW-H), Ten 3-month-old C57BL/6 J wild-type mice were randomly selected as the control group (C). The control and model groups were administered saline by gavage, the donepezil group was administered donepezil (0.92 mg/kg/d), and the KXSJW-low/medium/high dose group was administered KXSJW extract (0.9/1.8/3.6 mL/kg/d); each group was treated once daily for 2 months. The study employed the Morris Water Maze (MWM) to evaluate learning and cognitive abilities. Pathological changes in colon tissue were assessed through hematoxylin and eosin (HE) staining. Analysis of gut microbiota was conducted using 16S rRNA sequencing, and gut microbial metabolite (short chain fatty acids, SCFAs) content was detected using GC-MS. Colonic tissue barrier integrity was examined through immunohistochemistry and western blot, while β-amyloid deposition in brain tissue was assessed. ELISA was used to measure serum intestinal peptide hormones (Glucagon, GHRP-Ghrelin).

RESULTS: KXSJW enhanced learning ability and memory, reduced amyloid deposition in the brain tissue of AD model mice. KXSJW was able to restore the balance of intestinal flora and regulate the concentration of intestinal flora metabolites, especially represented by Firmicutes and its major metabolite butyric acid. Meanwhile, KXSJW restored the intestinal barrier function and improved the release level of intestinal peptide hormones (Glucagon, GHRP-Ghrelin) in AD model mice. This indicates that KXSJW can improve the intestinal internal environment of AD model mice.

CONCLUSION: KXSJW may improve the homeostasis of the gut environment in AD, with a focus on the regulation of gut microorganisms and their metabolites, and subsequently improve cognitive impairment in AD. Traditional Chinese Medicine (TCM) has the potential to intervene in AD through multilevel interaction with the brain-gut-axis.},
}

@article {pmid40350897,
year = {2025},
author = {Liu, X and Zhang, RB and Li, CX and Li, WL},
title = {[Research progress of treating Alzheimer's disease with traditional Chinese medicine].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {5},
pages = {1146-1154},
doi = {10.19540/j.cnki.cjcmm.20241111.601},
pmid = {40350897},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drugs, Chinese Herbal/therapeutic use ; *Medicine, Chinese Traditional ; Animals ; },
abstract = {Alzheimer's disease(AD) has a high incidence rate and insidious onset, and it is the main type of senile dementia, severely affecting the survival and death of patients. The main clinical manifestations include memory loss, aphasia, apraxias, agnosia, and changes in executive dysfunction, personality, and behaviors, and its pathogenesis is not yet clear. In recent years, there has been an increasing number of traditional Chinese medicine treatments for AD, including Chinese herbal compounds, external treatments of traditional Chinese medicine(TCM), and a combination of TCM and Western medicine, with significant efficacy and no obvious toxic side effects. Starting from the understanding of the pathogenesis of AD in TCM, this article comprehensively summarized the theoretical basis of TCM in treating the disease, providing a theoretical basis for clinical research.},
}

*Alzheimer Disease/drug therapy
Humans
*Drugs, Chinese Herbal/therapeutic use
*Medicine, Chinese Traditional
Animals

@article {pmid40349697,
year = {2025},
author = {Triplett, O and Varda, N and Decourt, B and Vasconcellos, R and Sabbagh, MN},
title = {Active immunization targeting amyloid β for the treatment of Alzheimer's disease.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-22},
doi = {10.1159/000546287},
pmid = {40349697},
issn = {1660-2862},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative condition worldwide. It is characterized by the formation of amyloid beta (Aβ) plaques in the brain and by the accumulation of neurofibrillary tangles; the disease is marked by cognitive decline and memory impairment over time. Although cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have been used to relieve symptoms, immunotherapies to treat the disease itself by targeting removal of amyloid are now beginning to be applied clinically. However, methods that allow the control of AD symptoms and that would require only a few clinical follow-ups are often preferred by patients. Thus, active immunization, or vaccination, against Aβ and tau is still being explored as a possible therapeutic intervention.

SUMMARY: This review aims to describe ongoing and discontinued immunization trials to treat AD. We conducted a comprehensive review of the literature to analyze the current status of vaccinations for AD. We examined and summarized the studies and clinical trials that explored the efficacy, safety, and challenges associated with this therapeutic approach.

KEY MESSAGES: This review highlights the potential for vaccination development to treat AD, including its efficacy, associated complications, and limitations. Much progress has been made over the past two decades, but challenges remain. Immunization is a promising avenue for treating or preventing symptomatic AD, offering potential benefits beyond symptomatic relief. Because challenges such as immunogenicity and safety profiles need to be addressed, further research and development is necessary to meet the growing demand for patient-acceptable, effective AD treatments.},
}

@article {pmid40349579,
year = {2025},
author = {Raj, S and Namdeo, V and Singh, P and Srivastava, A},
title = {Identification and prioritization of disease candidate genes using biomedical named entity recognition and random forest classification.},
journal = {Computers in biology and medicine},
volume = {192},
number = {Pt B},
pages = {110320},
doi = {10.1016/j.compbiomed.2025.110320},
pmid = {40349579},
issn = {1879-0534},
abstract = {BACKGROUND AND OBJECTIVE: The elucidation of candidate genes is fundamental to comprehending intricate diseases, vital for early diagnosis, personalized treatment, and drug discovery. Traditional Disease Gene Identification methods encounter limitations, necessitating substantial sample sizes and statistical power, particularly challenging for complex diseases. Conversely, Disease Gene Prioritization methods leverage biological knowledge but rely on computational predictions, often lacking experimental validation. Addressing existing tool challenges, this study introduces an innovative two-tier machine-learning protocol that distils Disease Gene Association details from disease-specific abstracts, incorporating diverse findings. Employing advanced text mining, the model classifies disease-gene associations from the abstracts into Positive, Negative, and Ambiguous classes.

METHODS: Leveraging Random Forest as a robust text classification tool, this study demonstrates its efficacy in navigating complexities within biomedical texts. In the developed 2-tiered protocol, the level 1 classifier categorizes information into two classes, distinguished by the presence or absence of disease-gene associations, whereas the level 2 classifier further classifies into three classes: Positive, Negative, and Ambiguous associations. The developed classifier underwent rigorous training and cross-validation on different gold standard datasets - Alzheimer's, Breast Cancer and Type 2 Diabetes. Its performance across these varied disease contexts underscores its versatility and robustness without succumbing to overfitting.

RESULTS: Achieving an average accuracy of 97.29 % and 98.14 % for level 1 and level 2 classification, the protocol successfully extracted 2769, 3220 and 740 genes associated positively with Alzheimer's, Breast Cancer and Type 2 Diabetes. From the identified positive genes, a substantial number-1008, 670, and 165 genes, respectively-were not reported in established databases, thus expanding the genetic exploration of these diseases. These identified genes offer promising opportunities for targeted interventions, while ambiguous genes warrant further investigation to unravel deeper disease associations.

CONCLUSIONS: This research significantly contributes to the understanding of genetic diseases by offering a comprehensive roadmap for their intricate exploration. Beyond the study's focus on Alzheimer's, Breast Cancer, and Type 2 Diabetes, the protocol's applicability extends to diverse biomedical landscapes, demonstrating its versatility and impactful potential for comprehensive disease exploration.},
}

@article {pmid40349564,
year = {2025},
author = {Negahdary, M and Sakthinathan, I and Mirsadoughi, E and Ligler, FS and Coté, GL and Forster, RJ and Mabbott, S},
title = {Advances in biosensors for diagnosis of Alzheimer's and Parkinson's diseases.},
journal = {Biosensors & bioelectronics},
volume = {284},
number = {},
pages = {117535},
doi = {10.1016/j.bios.2025.117535},
pmid = {40349564},
issn = {1873-4235},
abstract = {Early diagnosis by detecting ultralow concentrations of disease biomarkers is critical for timely treatment of the two most common neurodegenerative diseases, Alzheimer's and Parkinson's diseases. Innovative biosensors technologies can provide accurate, faster, and cheaper diagnostic pathways. In this review, the most recent electrochemical and optical sensing and biosensing platforms for diagnosing these diseases are critically selected and reviewed. Diagnostic targets (generally biomarkers) related to each disease and novel technologies, such as nanomaterials and biomolecular techniques to optimize the detection process and enhance signals, are discussed. In particular, multiplex detection and detection of multiple analytes by a (bio) sensing platform, to improve clinical sensitivity and selectivity are considered. This review is intended to open new approaches in the field and advance future research by identifying those strategies that optimize real-world performance and minimize present shortcomings.},
}

@article {pmid40349168,
year = {2025},
author = {Jiang, M and Li, Q and Chen, J and Li, R and Yao, J and Hu, Y and Zhang, H and Cai, L and Luo, M and Sun, Y and Zeng, W},
title = {Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2417733},
doi = {10.1002/advs.202417733},
pmid = {40349168},
issn = {2198-3844},
support = {32225019//National Natural Science Foundation of China/ ; 92357304//National Natural Science Foundation of China/ ; 32394003//National Natural Science Foundation of China/ ; 2023YFC2306300//National Key R&D Program of China/ ; },
abstract = {Alzheimer's disease (AD) is a predominant neurodegenerative disorder worldwide, with epileptic seizures being a common comorbidity that can exacerbate cognitive deterioration in affected individuals, thus highlighting the importance of early therapeutic intervention. It is determined that deletion of Ms4a4a, an AD-associated gene, exacerbates seizures in amyloid β (Aβ)-driven AD mouse model. MS4A4A is significantly upregulated in brain lesions in patients with epilepsy. Single-cell sequencing reveals that MS4A4A is highly expressed in microglia within these lesions, linked to enhanced phagocytic activity. Mechanistic investigation delineates that deletion of Ms4a4a impairs microglial phagocytosis, accompanied by diminished calcium influx and disruptions in mitochondrial metabolic fitness. The cytosolic fragment of Ms4a4a is anchored to the cytoskeletal components, supporting its critical role in mediating phagocytosis. Induction of Ms4a4a through central delivery of LNP-Il4 alleviates seizure conditions. Collectively, these findings identify Ms4a4a as a potential therapeutic target for managing seizures in AD treatment.},
}

@article {pmid40347934,
year = {2025},
author = {Hampel, H and Li, G and Mielke, MM and Galvin, JE and Kivipelto, M and Santarnecchi, E and Babiloni, C and Devanarayan, V and Tkatch, R and Hu, Y and Kurzman, R and Cho, M and Vandercappellen, J and Nakamura, Y and Bell, J and Mattke, S and Toschi, N},
title = {The impact of real-world evidence in implementing and optimizing Alzheimer's disease care.},
journal = {Med (New York, N.Y.)},
volume = {6},
number = {5},
pages = {100695},
doi = {10.1016/j.medj.2025.100695},
pmid = {40347934},
issn = {2666-6340},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/drug therapy ; *Cognitive Dysfunction/diagnosis ; Precision Medicine ; Early Diagnosis ; Biomarkers ; Electronic Health Records ; Evidence-Based Medicine ; },
abstract = {Real-world evidence (RWE) can complement clinical trials by addressing gaps in how approved anti-amyloid therapies for early Alzheimer's disease (AD) are used in everyday practice. This article outlines strategies to generate RWE that bridge three key challenges in AD care: low detection rates of mild cognitive impairment (MCI), limited data on long-term safety and effectiveness, and a lack of personalized treatment strategies. With MCI detection rates among primary care providers as low as 6%-15%, we propose cost-effective triage tools using electronic health records to enhance early diagnosis and intervention. We also highlight the importance of understanding anti-amyloid therapy outcomes in diverse, real-world populations. Supported by FDA initiatives, pragmatic trials and observational studies using real-world data (RWD) can help develop predictive models that incorporate biomarkers and support precision medicine. These approaches aim to move AD care beyond one-size-fits-all treatment, guiding more tailored, effective strategies for patients.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/drug therapy
*Cognitive Dysfunction/diagnosis
Precision Medicine
Early Diagnosis
Biomarkers
Electronic Health Records
Evidence-Based Medicine

@article {pmid40347851,
year = {2025},
author = {Du, B and Zou, Q and Wang, X and Wang, H and Yang, X and Wang, Q and Wang, K},
title = {Multi-targeted engineered hybrid exosomes as Aβ nanoscavengers and inflammatory modulators for multi-pathway intervention in Alzheimer's disease.},
journal = {Biomaterials},
volume = {322},
number = {},
pages = {123403},
doi = {10.1016/j.biomaterials.2025.123403},
pmid = {40347851},
issn = {1878-5905},
abstract = {The pathogenesis of Alzheimer's disease (AD) was complex, including excessive deposition of β-amyloid (Aβ), microglia dysfunction, and neuroinflammation. Therefore, single-pathway treatment was not sufficient to ameliorate the multifaceted pathological changes associated with AD. Moreover, the low permeability of blood-brain barrier (BBB) and the lack of AD locus selectivity further limited the intervention efficacy of current AD drugs. In this study, a novel nanoparticle coating was designed by hybridizing the membrane from brain microvascular endothelial cell exosomes and macrophage exosomes, and combining polydopamine nanoparticles, resveratrol and Aβ-targeting aptamers to construct engineered exosomes (RPDA@Rb-A) with multiple targeting capabilities to intervene in Aβ clearance and regulate microglial dysfunction. Based on the homing effect of brain microvascular endothelial cell exosomes and the natural inflammation targeting ability of macrophage exosomes, RPDA@Rb-A can easily penetrate the blood brain barrier and accumulate in the brain inflammation site after capturing Aβ aggregates. RPDA@Rb-A can effectively intervene in AD through multi-pathway, including degraded toxic Aβ aggregates through local heating induced by near-infrared laser irradiation and alleviated neurotoxicity, promoted microglial clearance of Aβ by capturing Aβ, and modulated microglia-induced neuroinflammation by efficient delivery of small molecule drugs. In AD mouse model, the administration of RPDA@Rb-A resulted in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. The engineered exosomes based on membrane hybridization overcome the shortcomings of traditional drug carriers in poor penetration and insufficient targeting to the central nervous system, and provide a potential platform for multi pathways intervention in AD.},
}

@article {pmid40347795,
year = {2025},
author = {Roy, P},
title = {Diverse mathematical approaches to Alzheimer's disease: Comment on "Mathematical models on Alzheimer's disease and its treatment: A review" by Mitali Maji & Subhas Khajanchi.},
journal = {Physics of life reviews},
volume = {53},
number = {},
pages = {316-317},
doi = {10.1016/j.plrev.2025.04.008},
pmid = {40347795},
issn = {1873-1457},
}

@article {pmid40347374,
year = {2025},
author = {Varshney, V and Gabble, BC and Bishoyi, AK and Varma, P and Qahtan, SA and Kashyap, A and Panigrahi, R and Nathiya, D and Chauhan, AS},
title = {Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40347374},
issn = {1559-1182},
abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.},
}

@article {pmid40346951,
year = {2025},
author = {Han, J and Song, J and Jung, ES and Choi, JW and Ji, HY and Mook-Jung, I},
title = {SGLT2 Inhibition by Enavogliflozin Significantly Reduces Aβ Pathology and Restores Cognitive Function via Upregulation of Microglial AMPK Signaling in 5XFAD Mouse Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70101},
doi = {10.1111/acel.70101},
pmid = {40346951},
issn = {1474-9726},
support = {RS-2020-KH106747//Korea Dementia Research Center/ ; RS-2020-KH106773//Korea Dementia Research Center/ ; //Daewoong Pharmaceutical Company/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Metabolic dysfunctions, particularly type 2 diabetes mellitus (T2DM), have been implicated in AD pathogenesis, highlighting the potential for novel therapeutic approaches targeting shared underlying mechanisms. Here, we investigate sodium-glucose cotransporter 2 (SGLT2) inhibition as a therapeutic strategy for AD using Enavogliflozin, a potent SGLT2 inhibitor, in the 5XFAD mouse model. Five-month-old 5XFAD mice were treated with Enavogliflozin (0.1 or 1 mg/kg) or vehicle for 8 weeks. The higher dose significantly improved cognitive performance in Y-maze and Morris Water Maze tests, which correlated with enhanced synaptic plasticity and increased acetylcholine levels. Moreover, Enavogliflozin treatment reduced Aβ pathology and plaque burden, particularly affecting larger plaques. Mechanistically, SGLT2 inhibition attenuated neuroinflammation by suppressing NF-κB signaling and proinflammatory cytokine production while promoting microglial recruitment to plaques. In vitro and ex vivo analyses further revealed that Enavogliflozin enhances microglial phagocytic capacity via AMPK-mediated mitochondrial biogenesis and function. These findings highlight the multifaceted neuroprotective effects of SGLT2 inhibition in AD, demonstrating its potential to mitigate pathology and improve cognitive function. By uncovering its impact on neuroinflammation and microglial function, this study establishes SGLT2 inhibition as a promising therapeutic avenue for AD and other neurodegenerative disorders.},
}

@article {pmid40346933,
year = {2025},
author = {Limban, C and Nuță, DC and Caproiu, MT and Dumitrescu, DE and Papacocea, ȘI and Bordei, AT and Dumitrașcu, F},
title = {Synthesis Methods and Therapeutic Journey of Carprofen and Its Derivatives: A Review.},
journal = {Chemical biology & drug design},
volume = {105},
number = {5},
pages = {e70122},
pmid = {40346933},
issn = {1747-0285},
support = {//University of Medicine and Pharmacy Carol Davila/ ; },
mesh = {Humans ; *Carbazoles/chemical synthesis/chemistry/therapeutic use/pharmacology ; *Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis/chemistry/therapeutic use/pharmacology ; Animals ; Antineoplastic Agents/chemical synthesis/chemistry/pharmacology/therapeutic use ; Anti-Infective Agents/chemical synthesis/chemistry/pharmacology/therapeutic use ; Antiviral Agents/chemical synthesis/chemistry/pharmacology/therapeutic use ; },
abstract = {Carprofen, a nonsteroidal anti-inflammatory drug (NSAID) derived from propanoic acid, is known for its analgesic and antipyretic properties. Although it has long been employed in veterinary medicine as an anti-inflammatory agent, its use in humans was discontinued shortly after its market launch due to costly raw materials, complex synthesis, and labor-intensive production processes-factors that made it less competitive compared with other NSAIDs. Despite this, the carprofen molecule remains a subject of significant scientific interest. Recent advancements in its synthesis have introduced simplified and more cost-effective methods, reigniting its potential for both novel applications and drug repurposing. Exciting new research is exploring carprofen's broader therapeutic possibilities, extending beyond its original anti-inflammatory role. Studies are investigating its efficacy in antimicrobial therapy-including antibiofilm, anticancer, antiviral, and anti-Alzheimer's applications-opening doors to a wealth of untapped possibilities. This review delves into these emerging areas, highlighting how carprofen's molecular structure and derivatives can be leveraged to expand its therapeutic reach. The literature review was conducted using four databases: Web of Science, ScienceDirect, Scopus, Embase, and Reaxys. The review focused on English-language original research and review articles, examining carprofen and its derivatives in terms of their synthesis methods as well as their use as small molecules in various therapeutic applications, both human and veterinary. With ongoing research pushing the boundaries of its potential, carprofen remains a promising candidate for innovation in drug development and treatment strategies.},
}

Humans
*Carbazoles/chemical synthesis/chemistry/therapeutic use/pharmacology
*Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis/chemistry/therapeutic use/pharmacology
Animals
Antineoplastic Agents/chemical synthesis/chemistry/pharmacology/therapeutic use
Anti-Infective Agents/chemical synthesis/chemistry/pharmacology/therapeutic use
Antiviral Agents/chemical synthesis/chemistry/pharmacology/therapeutic use

@article {pmid40346856,
year = {2025},
author = {Jia, P and Hao, Z and Yiu, K and Tsoi, K},
title = {Causal Effects Between Blood Pressure Variability and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.},
journal = {Journal of clinical hypertension (Greenwich, Conn.)},
volume = {27},
number = {5},
pages = {e70066},
pmid = {40346856},
issn = {1751-7176},
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology/physiopathology ; Mendelian Randomization Analysis/methods ; Genome-Wide Association Study/methods ; *Blood Pressure/genetics/physiology ; Polymorphism, Single Nucleotide/genetics ; Male ; Genetic Predisposition to Disease ; Female ; United Kingdom/epidemiology ; Risk Factors ; Aged ; *Hypertension/genetics/epidemiology ; },
abstract = {Alzheimer's disease (AD), an escalating global public health concern, demonstrates complex pathogenesis involving both genetic predisposition and vascular components. Blood pressure variability (BPV) has been implicated in neurodegenerative diseases, but its causal relationship with AD remains unclear. This study aims to explore the causal relationship between BPV and AD by applying Mendelian randomization (MR) to genome-wide association study (GWAS) summary data. Genetic instruments were selected from BPV GWAS based on UK Biobank data, ensuring relevance and significance(p < 5 × 10[-6]). Genetic estimates on exposure were obtained from three databases: The The International Genomic of Alzheimer's Project (IGAP); Maternal family history of AD from UK Biobank (MFH-UKBB), and Paternal family history of AD from UK Biobank (PFH-UKBB). Proxy SNPs were manually selected if SNPs were not available in the exposure GWAS. Data harmonization was performed to ensure consistency in effect and reference alleles. Three MR statistical methods were employed to assess causal effects, including inverse variance weighting (IVW) with random or fixed effect, MR-Egger regression, and the Weighted Median Method. Sensitivity analyses to evaluate robustness were also employed. Six SNPs associated with systolic BPV and six SNPs associated with diastolic BPV were included. Significant causal effects of SBPV on AD were found on the PFH-UKBB dataset in all four methods. The odds ratios for AD per 10-unit increment in SBPV were 1.028, 1.015, and 1.015 for MR-Egger, IVW-MR, and weighted median, respectively. In contrast, only IVW methods found significant results for DBPV in the MFH-UKBB dataset. SBPV is a possible causal risk factor for AD, while the evidence for DBPV needs further study. BPV control should be an important treatment target in preventing dementia.},
}

Humans
*Alzheimer Disease/genetics/epidemiology/physiopathology
Mendelian Randomization Analysis/methods
Genome-Wide Association Study/methods
*Blood Pressure/genetics/physiology
Polymorphism, Single Nucleotide/genetics
Male
Genetic Predisposition to Disease
Female
United Kingdom/epidemiology
Risk Factors
Aged
*Hypertension/genetics/epidemiology

@article {pmid40347768,
year = {2025},
author = {Liu, X and Xu, J and Yu, C and Dai, C and Chen, J and Zhong, J and Yang, Y and Lin, H and Chen, X and Zhang, Q and Dai, L and Zhang, J and Zha, D and Ye, ZC},
title = {A novel carbamate-based hybrid derivative with anti-neuroinflammatory properties as a selective butyrylcholinesterase inhibitor for Alzheimer's disease therapy.},
journal = {Bioorganic chemistry},
volume = {161},
number = {},
pages = {108551},
doi = {10.1016/j.bioorg.2025.108551},
pmid = {40347768},
issn = {1090-2120},
abstract = {Cholinesterase inhibitors (ChEIs) are widely utilized for the symptomatic management of Alzheimer's disease (AD) by enhancing acetylcholine levels to improve cognitive function. Concurrently, neuroinflammation has emerged as a critical factor in AD progression, necessitating therapies that address this pathology. In this study, we designed and synthesized a novel bifunctional cholinesterase inhibitor, (E)-4-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl) vinyl)-1,2-phenylene bis(ethyl(methyl)carbamate) (D40), which combines potent cholinesterase inhibition with robust anti-neuroinflammatory activity. D40 demonstrated potent inhibition of human butyrylcholinesterase (hBuChE), with an IC50 value of 0.59 ± 0.03 μM, significantly outperforming Rivastigmine (IC50 = 3.70 ± 0.96 μM). Molecular docking and molecular dynamics simulations confirmed a stable and selective binding of D40 to the BuChE active site, underpinning its inhibitory profile. Additionally, D40 exhibited strong anti-inflammatory effects, with an IC50 value of 4.55 ± 0.78 μM for suppressing nitric oxide production and demonstrated excellent blood-brain barrier permeability. In vivo studies in aged 5 × FAD mice revealed that D40 significantly reduced neuroinflammation by suppressing pro-inflammatory cytokines and glial activation. Furthermore, D40 mitigated Aβ deposition, promoted neuronal survival, and improved cognitive deficits, while demonstrating a favorable safety profile in acute toxicity evaluations. These findings highlight D40 as a dual-function ChEI capable of providing symptomatic relief and modulating neuroinflammatory pathways associated with AD. With its enhanced cholinesterase inhibition and anti-inflammatory properties, D40 emerges as a promising candidate for the treatment of advanced stages of AD. Acetylcholine deficiency and neuroinflammation as drivers of Alzheimer's disease dually intervened by Compound D40.},
}

@article {pmid40347723,
year = {2025},
author = {Lv, B and Wang, Z and Wang, Q and Xu, Z and Tang, J and Pei, Y and Bian, Y and Sun, H and Chen, Y},
title = {Dual inhibitors of butyrylcholinesterase and histone deacetylase 6 for the treatment of Alzheimer's disease: design, synthesis, and biological evaluation.},
journal = {Bioorganic & medicinal chemistry},
volume = {127},
number = {},
pages = {118219},
doi = {10.1016/j.bmc.2025.118219},
pmid = {40347723},
issn = {1464-3391},
abstract = {To address the multifactorial pathology of Alzheimer's disease (AD), eighteen butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) dual inhibitors were designed, synthesized, and biologically evaluated. Through structure-activity relationship studies, compound 17 emerged as the most potent candidate, with IC50 value of 0.3 nM for human BChE and 56.7 nM for HDAC6. This compound demonstrated favorable safety profiles, drug-like properties, and significant neuroprotective effects in vitro. In a mouse model of scopolamine-induced cognitive impairment, 17 (10 mg/kg) exhibited excellent safety and markedly improved cognitive deficits. These findings highlight compound 17 as a promising BChE/HDAC6 dual inhibitor, supporting its further development as a potential therapeutic agent for AD.},
}

@article {pmid40346804,
year = {2025},
author = {Mostafa, A and Tiu, S and Khan, F and Baig, NA},
title = {The Efficacy of Anti-amyloid Monoclonal Antibodies in Early Alzheimer's Dementia: A Systematic Review.},
journal = {Annals of Indian Academy of Neurology},
volume = {},
number = {},
pages = {},
doi = {10.4103/aian.aian_547_24},
pmid = {40346804},
issn = {0972-2327},
abstract = {INTRODUCTION: Much research has been conducted into the role and safety of anti-amyloid monoclonal antibodies on the progression of Alzheimer's disease (AD). Despite the historical approval of three drugs by the US Food and Drug Administration for the treatment of early AD, there remains other potential treatment, which is yet to be approved or further developed. This systematic review explores the efficacy of anti-amyloid monoclonal antibodies in the treatment of early AD from reported clinical trials.

METHODS: Authors conducted a systematic search of MEDLINE and Embase. Screening was carried out by two authors and cross-checked thereafter. Clinical changes in cognition and objective measures such as cerebrospinal fluid biomarkers and imaging constituted primary and secondary outcomes, respectively.

RESULTS: Our search yielded 14 randomized controlled trials; the primary focus of the included trials is amyloid-β. The monoclonal antibodies reported in this review are: lecanemab, aducanumab, crenezumab, solanezumab, donanemab, bapineuzumab, and gantenerumab. The most common finding among the trials is the lack of statistically significant results in measures of clinical outcomes, (e.g., Clinical Dementia Rating Scale-Sum of Boxes, AD Assessment Scale-Cognitive Subscale). However, specific trials investigating lecanemab, aducanumab, and donanemab demonstrated promising improvements in clinical cognition. Results related to secondary outcomes were also mixed, but showed more positive findings across the included trials. Overall, primary outcomes were inconsistent with secondary outcomes.

CONCLUSION: Our findings highlight the need to consider the complex pathophysiology of AD in treatment development. Focusing solely on the amyloid-beta hypothesis may be inadequate; further research is necessary to understand the underlying mechanisms and develop treatments for the multifactorial nature of the disease.},
}

@article {pmid40346511,
year = {2025},
author = {Shiotani, M and Hyohdoh, Y and Hatakeyama, Y and Kazui, H and Okuhara, Y},
title = {Identifying suppressive factors of Alzheimer's disease through comprehensive analysis of real-world data: a single-center retrospective study.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {321},
pmid = {40346511},
issn = {1471-2318},
support = {JP20K21715//Japan Society for the Promotion of Science/ ; JP20K21715//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis/drug therapy/prevention & control ; Retrospective Studies ; Male ; Female ; Aged ; Japan/epidemiology ; Aged, 80 and over ; *Glycyrrhizic Acid/therapeutic use ; },
abstract = {BACKGROUND: In addition to conventional symptomatic treatment drugs, anti-amyloid beta antibody drugs are expected to benefit patients with Alzheimer's disease (AD). However, issues such as side effects and high costs persist, and new preventive and therapeutic drugs are desired. Meanwhile, information on the diagnosis and symptomatic treatment of AD accumulated during daily clinical practice is stored as real-world data and is considered a powerful means of discovering unknown factors that could provide clues for new prevention and treatment approaches for AD through comprehensive exploration.

METHODS: We used anonymized hospital information system data from a tertiary care and academic hospital in Japan, spanning from 1981 to 2016, to search for potential suppressive factors for AD onset and to verify the validity of the discovered factors. We initially conducted a comprehensive search for candidate suppressive factors for AD and verified them using the inverse probability weighting (IPW) method with propensity scores.

RESULTS: From the comprehensive search, we identified glycyrrhizic acid (GA), a component of licorice, a traditional medicine with anti-inflammatory, antioxidant, antibacterial, and antiaging properties, as a candidate suppressing factor for AD. The IPW method showed that the odds ratio of developing AD in the GA group was 0.642 (95% confidence interval: 0.566-0.727) compared with the non-GA group after adjustment.

CONCLUSIONS: This is the first human study to suggest that GA may be a factor that can suppress the onset of AD. Additionally, our method could be a promising tool for drug repositioning that applies existing drugs already used in clinical settings with well-known side effects to diseases different from their original use.},
}

Humans
*Alzheimer Disease/epidemiology/diagnosis/drug therapy/prevention & control
Retrospective Studies
Male
Female
Aged
Japan/epidemiology
Aged, 80 and over
*Glycyrrhizic Acid/therapeutic use

@article {pmid40346444,
year = {2025},
author = {Dharshan, SS and R, M and Rao, SM and Aswinanand, B and Ramamurthy, K and Muthuramamoorthy, M and Arasu, MV and Kumaradoss, KM and Guru, A and Palaniappan, S and Arockiaraj, J},
title = {SG06, a Chalcone Derivative Targets PI3K/AKT1 Pathway for Neuroprotection and Cognitive Enhancement in an Alzheimer's Disease-Like Zebrafish Model.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40346444},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) and Alzheimer's dementia (ADM) are common neurodegenerative disorders marked by progressive cognitive decline, memory impairment, and behavioral deficits, which impose a significant burden on individuals and healthcare systems worldwide. Due to the complex nature of AD pathophysiology, effective treatment strategies may require targeting multiple pathways. This study explored the neuroprotective effects of the chalcone derivative SG06 in a scopolamine-induced AD-like zebrafish model using network pharmacology and molecular docking. SG06 showed strong binding to key targets such as AKT serine/threonine kinase 1 (AKT1), which are involved in processes like tau phosphorylation, amyloid-beta (Aβ) production, and inflammation. Behavioral assays indicated that SG06 improved cognitive function, reduced anxiety-like behavior, and restored social interactions. Additionally, sensory recovery was observed through better light/dark transitions and recovered olfactory function, likely due to improved neuronal communication and reduced oxidative stress. Mechanistically, SG06 appeared to activate the PI3K/AKT1 pathway, inhibiting Glycogen Synthase Kinase 3 beta (GSK3β) activity, which may help reduce tau hyperphosphorylation and amyloid processing. SG06 also restored antioxidant markers (CAT, GSH, GPx) and improved acetylcholinesterase (AChE) activity, reducing oxidative damage and cholinergic dysfunction. Histological analysis revealed improved cellular morphology and decreased Aβ plaque accumulation, while gene expression studies showed downregulation of pro-inflammatory markers and upregulation of neuroprotective genes. Additionally, SG06 helped improving neurotransmitter balance, particularly in Gamma-Aminobutyric Acid (GABA) and Dopamine (DPAN), contributing to improved synaptic plasticity and cognitive function. These findings suggest that SG06 may have potential as a multi-target therapeutic agent in addressing the complex pathology of AD.},
}

@article {pmid40345981,
year = {2025},
author = {Panteleienko, L and Mallon, D and Htet, CMM and Lizak, N and Zandi, M and Banerjee, G and Werring, DJ},
title = {Cerebral Amyloid Angiopathy-Related Inflammation in Iatrogenic Cerebral Amyloid Angiopathy.},
journal = {European journal of neurology},
volume = {32},
number = {5},
pages = {e70198},
doi = {10.1111/ene.70198},
pmid = {40345981},
issn = {1468-1331},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/complications/diagnostic imaging/pathology ; Iatrogenic Disease ; *Inflammation/etiology ; Aged ; Cerebral Hemorrhage/etiology ; Male ; Female ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) related inflammation (CAA-ri) is considered to be a distinct syndrome caused by an inflammatory response to amyloid-β deposition in the walls of small leptomeningeal and cortical vessels in patients with sporadic CAA. However, recent data suggest that inflammation might contribute to a broader range of CAA subtypes.

RESULTS: We describe a case of probable iatrogenic CAA (iCAA), which manifested with multiple intracerebral haemorrhages complicated by the development of clinical and radiological features of CAA-ri, which responded to steroids. Clinical, neuroimaging and CSF data suggested possible co-existing Alzheimer's pathology.

DISCUSSION: CAA-ri may occur in association with iCAA, suggesting that a broader spectrum of patients might benefit from steroid treatment than previously assumed.},
}

Humans
*Cerebral Amyloid Angiopathy/complications/diagnostic imaging/pathology
Iatrogenic Disease
*Inflammation/etiology
Aged
Cerebral Hemorrhage/etiology
Male
Female

@article {pmid40345388,
year = {2025},
author = {Fotovat-Ahmadi, N and Siddiqui, O and Ong, J and Thanitcul, C and Reinhardt, C and Cologna, SM and Aakalu, VK},
title = {The Ocular Surface Tear Film as a Biomarker for Systemic Health.},
journal = {The ocular surface},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtos.2025.05.005},
pmid = {40345388},
issn = {1937-5913},
abstract = {The tear film is a complex structure with rich interactions with the human body. A growing body of evidence suggests that measuring changes in protein, lipid, or other metabolite concentration in the tear film can be used to help detect disease. Particularly in the era of precision medicine, the tear film serves as a promising source of non-invasive insights into systemic health for early diagnosis and treatment. This paper analyzes the latest research in tear film biomarkers for systemic diseases. The review was conducted through PubMed and Embase databases using the PRISMA protocol and includes 54 articles. This paper first reviews the anatomy and physiology of tear film, as well as the latest proteomic analysis techniques on the tear film. We then provide a disease-by-disease review on the tear film as a biomarker including 5 articles related to Alzheimer's Disease, 10 articles related to Cancers, 1 article related to Cystic Fibrosis, 1 article related to Migraines, 4 articles related to Multiple Sclerosis, 15 articles related to Parkinson's Disease, 7 articles related to Rheumatoid Arthritis, and 11 articles related to Thyroid Disease. This paper highlights the promising results of these studies yet also reviews the challenges with limited sample sizes, reproducibility, and biological understanding of biomarkers. We conclude this paper with insights for future work to ensure clinical validity and generalizability. Ultimately, the tear film is a clinically accessible, complex structure that provides a wealth of information that may contribute to a more comprehensive understanding of systemic health.},
}

@article {pmid40345272,
year = {2025},
author = {Adedayo, LD and Aitokhuehi, NG and Bamidele, O and Adekeye, AO and Ajayi, AM and Onasanwo, SA},
title = {Buchholzia coriacea seed attenuates scopolamine-induced memory impairment in Mice by down-regulating oxidative stress biomarkers.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {119882},
doi = {10.1016/j.jep.2025.119882},
pmid = {40345272},
issn = {1872-7573},
abstract = {Amnesia is a common feature of neurodegenerative disorders. The seeds of Buchholzia coriacea have been traditionally employed to treat various diseases, including inflammatory conditions, pain, infections, and neurological disorders.

AIM: This study aimed to investigate the anti-amnesic and antioxidant potentials of methanol extract of Buchholzia coriacea seed (MEBC) in mice.

METHODS: Memory impairment was induced with scopolamine at 3 mg/kg, which was administered i.p. Thirty (30) male Swiss mice (23-27 g) were divided into 6 treatment groups (n=5): vehicle (10 mL/kg), scopolamine (3 mg/kg, i.p.), MEBC (50, 100, 200 mg/kg, p.o.), and donepezil (reference drug 1 mg/kg, p.o.), respectively. Memory function was assessed using the Morris Water Maze Test (MWMT) and the Y-maze Test (YMT). On the 7th day of administration, AchE, MDA, GSH, catalase, and nitrite were estimated to evaluate the neuroprotective action of Buchholzia coriacea via AchE inhibition and antioxidant activity. The hippocampus and prefrontal cortex were grossed for histological analysis.

RESULTS: The scopolamine treatment resulted in a decrease in percentage alternation, whereas mice pre-treated with MEBC prior to scopolamine had increased percentage alternation in YMT. The mean target quadrant time was significantly increased in the mice pretreated with MEBC. During the probe trial, mice administered with scopolamine had increased search error and chance level of time spent in the target quadrant region. However, MEBC pre-treated mice prior to scopolamine administration had increased latency time in the platform region in MWMT. Scopolamine-mediated changes in MDA and catalase activity were significantly attenuated by MEBC. There is an increased neuronal cell count of the hippocampus and prefrontal cortex region in groups treated with MEBC.

CONCLUSION: The findings suggest that MEBC seems to be a potent neuropharmacological agent against amnesia, and its mechanism(s) might be modulation of lipid peroxidation and oxidative stress activity associated with the Alzheimer type of amnesia.},
}

@article {pmid40345230,
year = {2025},
author = {Nitrini, R and Studart-Neto, A},
title = {Monoclonal antibodies against beta-amyloid protein (lecanemab and donanemab) should not be used in the treatment of Alzheimer's disease.},
journal = {Arquivos de neuro-psiquiatria},
volume = {83},
number = {5},
pages = {1-5},
doi = {10.1055/s-0045-1808082},
pmid = {40345230},
issn = {1678-4227},
abstract = {Two antiamyloid monoclonal antibodies (mAbs), lecanemab and donanemab, were recently launched for treatment of Alzheimer's disease (AD). These mAbs remove amyloid protein from the brain and cause statistically significant improvement in cognitive/functional tests, meaning a change in evolution of AD. This is important to reinforce the amyloid cascade hypothesis and to further concentrate studies on the pathways from the deposition of the beta-amyloid protein to synaptic loss and neuronal death. However, it is necessary to evaluate whether the results are clinically important. Analysis of the clinical trials showed that the statistically significant differences over placebo did not reach the minimum clinically important difference that would be meaningful for patients, caregivers and clinicians. Besides, the incidence of adverse events is high and potentially severe. Although there are reasons to celebrate this first step towards disease-modifying therapies for AD, lecanemab and donanemab should not be used to treat AD in clinical pratice.},
}

@article {pmid40344412,
year = {2025},
author = {Liu, H and Liu, X and Tian, F and Chen, Y and Li, J and Wang, X and Qiu, W and Wang, X and Ma, C and Ge, W},
title = {PRMT3-Mediated H4R3me2a Promotes Primary Age-Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2506044},
doi = {10.1002/advs.202506044},
pmid = {40344412},
issn = {2198-3844},
support = {82471222//National Natural Science Foundation of China/ ; 92353302//National Natural Science Foundation of China/ ; CIFMS 2021-I2M-1-025//CAMS Innovation Fund for Medical Sciences/ ; 2021ZD0201100//STI2030-Major Project/ ; 3332024152//Fundamental Research Funds for the Central Universities/ ; },
abstract = {Primary age-related tauopathy (PART) and Alzheimer's disease (AD) both exhibit 3R/4R hyperphosphorylated tau-positive neurofibrillary tangles (NFTs) within the hippocampal-entorhinal system. Notably, PART patients show a higher degree of tau hyperphosphorylation in the entorhinal cortex (EC) than AD, yet the molecular mechanisms driving Aβ-independent tau hyperphosphorylation in PART remain poorly understood. Herein, through transcriptomic profiling of postmortem EC tissues and in vitro and in vivo functional validation, the present study identifies protein arginine methyltransferase 3 (PRMT3) as a critical driver of tau hyperphosphorylation. Mechanistically, PRMT3-mediated tau hyperphosphorylation is dependent on asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2a), which upregulates miR-448. Elevated miR-448 specifically targets and suppresses IGF1R, leading to downstream GSK3β activation and subsequent tau hyperphosphorylation through PI3K/AKT/GSK3β signaling. Treatment with SGC707, a selective PRMT3 inhibitor, effectively reduces tau hyperphosphorylation and demonstrates therapeutic promise for PART and potentially other tauopathies. Collectively, this study defines the PRMT3/H4R3me2a/miR-448 axis as a critical regulatory pathway in tau hyperphosphorylation within PART, underscoring the potential of PRMT3 inhibition as a targeted therapeutic strategy for tauopathies.},
}

@article {pmid40344388,
year = {2025},
author = {Bachhav, SS and Ponce-Bobadilla, AV and Clausznitzer, D and Stodtmann, S and Xiong, H},
title = {Use of Model-Based Meta-Analysis to Inform the Design of Early Clinical Trials of Anti-Amyloid Beta Therapies in Alzheimer's Disease.},
journal = {CPT: pharmacometrics & systems pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/psp4.70038},
pmid = {40344388},
issn = {2163-8306},
abstract = {To inform an efficient development of new investigational anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs), a modeling-and-simulation-based strategy was proposed. A general modeling framework that links drug exposures to the time course of amyloid plaque removal and amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-E) was developed based on publicly available data on aducanumab, lecanemab, and donanemab. A non-linear mixed effect model with shared model parameters described the dose response data from aducanumab, lecanemab, and donanemab studies after adjusting for different potency for different antibodies, which allowed the rate of amyloid plaque removal to vary by drug. A time-to-event model was developed to describe ARIA-E incidence. The model assumes that ARIA-E incidence rate is dependent on the rate of amyloid plaque removal with a drug-dependent scaling factor linking amyloid plaque removal rate and treatment-dependent hazard. Simulations of amyloid plaque removal and ARIA-E for a hypothetical anti-Aβ mAb based on certain assumptions and scenarios provided insights into possible outcomes. Overall, the meta-analysis of published data on existing anti-Aβ mAbs could be utilized to model exposure-response relationships and the time course of amyloid plaque removal and ARIA-E incidence of new anti-Aβ mAbs and to inform the design of early clinical trials for them.},
}

@article {pmid40344229,
year = {2025},
author = {Ribeiro, RFN and Santos, MR and Aquino, M and de Almeida, LP and Cavadas, C and Silva, MMC},
title = {The Therapeutic Potential of Melatonin and Its Novel Synthetic Analogs in Circadian Rhythm Sleep Disorders, Inflammation-Associated Pathologies, and Neurodegenerative Diseases.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.22117},
pmid = {40344229},
issn = {1098-1128},
support = {//This study was funded by European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalisation (COMPETE 2020) and Portuguese national funds via Fundação para a Ciência e a Tecnologia (FCT), under projects UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020. R.F.N.R. is funded by FCT (2020.04850.BD)./ ; },
abstract = {Melatonin, N-acetyl-5-methoxytryptamine, is a tryptophan-derived hormone mostly produced in the pineal gland, despite being synthesized locally at several tissues and organs. This production is rhythmically controlled by complex clock gene networks in the master pacemaker located in the suprachiasmatic nucleus of the hypothalamus. Melatonin is usually secreted only during the dark phase of the day and is essential to synchronize circadian rhythms and neuroendocrine physiological processes. Its main clinical use is associated with the treatment of jet lag and other circadian rhythm sleep disorders, with a growing number of other promising therapeutic applications due to the diverse physiological roles of melatonin. In this review, we explore melatonin and its receptors and provide an updated overview on research concerning the role of melatonin, either as an endogenous molecule or as a drug, in: sleep-wake cycle regulation; circadian rhythms; inflammatory processes that may compromise cardiovascular, respiratory, gastrointestinal, renal, and reproductive system functions; and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The most recent and promising research findings concerning melatonin synthetic analogs such as agomelatine and ramelteon are highlighted, pointing toward new compounds with promising pharmacological activity while emphasizing their structural differences and advantages when compared to melatonin.},
}

@article {pmid40343695,
year = {2025},
author = {Oliva, HNP and Prudente, TP and Mayerson, TF and Mignosa, MM and Oliva, IO and Potenza, MN and Jegede, OO and Angarita, GA},
title = {Safety of Stimulants Across Patient Populations: A Meta-Analysis.},
journal = {JAMA network open},
volume = {8},
number = {5},
pages = {e259492},
doi = {10.1001/jamanetworkopen.2025.9492},
pmid = {40343695},
issn = {2574-3805},
abstract = {IMPORTANCE: The use of stimulant medications has expanded substantially beyond the traditional treatment of attention-deficit/hyperactivity disorder (ADHD) to encompass a variety of other clinical conditions. Understanding the safety of these medications is important as their use increases across diverse patient populations.

OBJECTIVE: To assess the safety of stimulant medications as reported in randomized clinical trials (RCTs) investigating methylphenidate, lisdexamfetamine, and other amphetamines.

DATA SOURCES: A comprehensive literature search was conducted from July 1, 2024, through February 28, 2025, using CINAHL, Embase, PubMed or MEDLINE, ScienceDirect, and Web of Science for studies published since 2000. Keywords included safety, adverse event, side effect, amphetamine, dextroamphetamine, stimulant, lisdexamfetamine, and methylphenidate.

STUDY SELECTION: RCTs published between January 1, 2000, and December 13, 2024, were included. These trials investigated the safety of stimulants in various clinical conditions, including ADHD, depression, binge eating disorder, schizophrenia, Alzheimer disease, and stimulant use disorders as well as in healthy individuals. Trials not focused on safety or adverse events (AEs) of stimulants, nonoriginal research, nonhuman research, trials with concomitant prescriptions other than stimulants, and trials without a placebo group were excluded.

DATA EXTRACTION AND SYNTHESIS: Data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Independent reviewers extracted study data, and a random-effects model was used to pool results. Heterogeneity was assessed using the I2 statistic.

MAIN OUTCOMES AND MEASURES: The primary outcome was the risk ratio (RR) of developing any AE in participants taking stimulants vs placebo.

RESULTS: A total of 93 RCTs were included after exclusions. The methodological quality assessment of the included trials showed overall low or unclear risk of bias. Trials with a duration of up to 52 weeks showed that stimulant medications were associated with an increased risk of overall AEs compared with placebo (RR, 1.34; 90% CI, 1.27-1.41), with high heterogeneity (I2 = 67%). Statistical significance of this finding was maintained when subgroups (ie, methylphenidate, lisdexamfetamine, and other amphetamines) were separately analyzed.

CONCLUSIONS AND RELEVANCE: This meta-analysis found an increased risk of overall AEs associated with stimulants compared with placebo. Future research could provide more standardized and consistent assessments of this outcome and may improve understanding about misuse risk.},
}

@article {pmid40343640,
year = {2025},
author = {Wakao, H and Iizuka, T and Shimizu, A},
title = {Improvements in dementia classification for brain SPECT volumes using vision transformer and the Brodmann areas.},
journal = {International journal of computer assisted radiology and surgery},
volume = {},
number = {},
pages = {},
pmid = {40343640},
issn = {1861-6429},
abstract = {PURPOSE: This study proposes a vision transformer (ViT)-based model for dementia classification, able to classify representative dementia with Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and healthy controls using brain single-photon emission computed tomography (SPECT) images. The proposed method allows for an input based on the anatomical structure of the brain and the efficient use of five different SPECT images.

METHODS: The proposed model comprises a linear projection of input patches, eight transformer encoder layers, and a multilayered perceptron for classification with the following features: 1. diverse feature extraction with a multi-head structure for five different SPECT images; 2. Brodmann area-based input patch reflecting the anatomical structure of the brain; 3. cross-attention to fusion of diverse features.

RESULTS: The proposed method achieved a classification accuracy of 85.89% for 418 SPECT images from real clinical cases, significantly outperforming previous studies. Ablation studies were conducted to investigate the validity of each contribution, in which the consistency between the model's attention map and the physician's attention region was analyzed in detail.

CONCLUSION: The proposed ViT-based model demonstrated superior dementia classification accuracy compared to previous methods, and is thus expected to contribute to early diagnosis and treatment of dementia using SPECT imaging. In the future, we aim to further improve the accuracy through the incorporation of patient clinical information.},
}

@article {pmid40343003,
year = {2025},
author = {Sun, Y and Bai, G and Yang, K and Feng, Y and Sun, H and Xian, L and Gao, H},
title = {Multi-target neuroprotection by dl-PHPB in APP/PS1 mice: a proteomic analysis.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1554168},
doi = {10.3389/fphar.2025.1554168},
pmid = {40343003},
issn = {1663-9812},
abstract = {INTRODUCTION: Dl-PHPB [potassium 2-(1-hydroxypentyl) benzoate] demonstrates robust neuroprotective effects in preclinical models of Alzheimer's disease (AD), significantly ameliorating cognitive deficits and pathological hallmarks. However, the underlying mechanism remains largely unclear. The current study primarily focused on elucidating dl-PHPB's neuroprotective mechanisms and identifying potential targets in preclinical AD models.

METHODS: Comparative proteomic analyses were performed on APP/PS1 mice orally administered either dl-PHPB (30 mg/kg) or vehicle daily for 3 months, alongside vehicle-treated wild-type (WT) non-transgenic littermates as controls. Total proteins were separated using two dimensional difference gel electrophoresis, and differentially expressed protein spots were identified via LC-MS/MS.

RESULTS AND DISCUSSION: Our results revealed 11 altered proteins in the cortex and 10 in the hippocampus between the WT and APP/PS1 groups treated with vehicle. Following dl-PHPB treatment, 12 differentially expressed proteins were identified in the cortex and 9 in the hippocampus of APP/PS1 mice. These proteins are primarily involved in energy metabolism, neuronal structure, protein trafficking, inflammatory and oxidative responses, and amyloid β (Aβ) and Tau processes, among which several proteins were validated as potential therapeutic targets. Notably, the expression levels of cofilin-2 and VDAC1 in APP/PS1 mice were restored to near-normal levels by the treatment with dl-PHPB, memantine, or donepezil, and further clinical validation is required to establish their utility as AD biomarkers for therapeutic efficacy.},
}

@article {pmid40342728,
year = {2025},
author = {Bibi, A and Yu, Z and Cui, L and Yang, G},
title = {Harnessing monocyte dynamics for treatment of multiple sclerosis; insights from experimental model studies.},
journal = {Immunotherapy advances},
volume = {5},
number = {1},
pages = {ltaf003},
doi = {10.1093/immadv/ltaf003},
pmid = {40342728},
issn = {2732-4303},
abstract = {Monocytes are central to the innate immune system's response to infection or injury. In murine, these cells are classified into distinct subsets: classical monocytes, defined by elevated Ly6C expression (Ly6C[hi]), intermediate monocytes (Ly6C[int]), and non-classical inflammatory monocytes, characterized by low Ly6C expression (Ly6C[low]). Monocytes recruited to tissues differentiate into macrophages, which can be pro-inflammatory or anti-inflammatory, thereby influencing disease processes and outcomes. The principal function of classical monocytes is the mediation of pro-inflammatory reactions, whereas non-classical monocytes are associated with repair and anti-inflammatory processes, patrolling the lumen of the vessels. Growing evidence highlights the importance of monocytes in multiple sclerosis (MS), an autoimmune and neurodegenerative disease of the central nervous system (CNS). Recent studies indicate that modulation of the innate immune system, focusing specifically on the shift from Ly6C[hi] to Ly6C[low] monocytes, is an effective therapeutic strategy for neurodegenerative diseases, such as Alzheimer's and MS. This transition is crucial for switching the immune response from inflammation to tissue repair and inflammation resolution, emphasizing the plasticity of monocytes and their potential as targets in MS. This review differs from prior studies in that it focuses solely on animal models of MS, which either directly perturb or study monocytes, or where therapeutic approaches mediate their protective effects through monocytes. Such details permit a subtle comprehension of monocyte dynamics in the context of MS.},
}

@article {pmid40341631,
year = {2025},
author = {Al-Sawasany, AS and Fayed, HM and Mahmoud, BF and Elblehi, SS and Ghazal, NA},
title = {Evaluation of the Neurotherapeutic Effect of Quercetin on Neuronal miR-124 and β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) in an Experimental Alzheimer's Disease Model.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {5},
pages = {e70290},
doi = {10.1002/jbt.70290},
pmid = {40341631},
issn = {1099-0461},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Animals ; *Quercetin/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; Male ; Rats ; *MicroRNAs/metabolism ; *Aspartic Acid Endopeptidases/metabolism ; Disease Models, Animal ; *Amyloid Precursor Protein Secretases/metabolism ; Rats, Wistar ; *Neurons/metabolism/pathology/drug effects ; Donepezil/pharmacology ; Hippocampus/metabolism/drug effects/pathology ; *Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, a neurodegenerative disorder that progress overtime, which is best known for mood swings and loss of cognitive, behavioral and functional abilities. Quercetin is one of the most consumed flavonoids in the diet and has neuroprotective, anti-inflammatory and antioxidant effects. The purpose of this study was to assess the potential neurotherapeutic effect of quercetin and compare it with donepezil. 40 Wister male rats were used and separated into two main groups: Group I: control group; Group II: AD group, which was divided into four subgroups: Group IIA: untreated AD-rats; Group IIB: quercetin treated AD-rats; Group IIC: donepezil treated AD-rats and Group IID: combined group of quercetin and donepezil. Hydrated aluminum chloride (AlCl3.6H2O) solution (75 mg/kg/day) was administered orally for 6 weeks to induce the AD-like conditions. Morris water maze, behavior test, was used to monitor the cognitive function. Hippocampal tissues were excised for assessment of Alzheimer's parameters and blood samples were obtained for liver and kidney function assessment. According to the final findings, untreated rats presented significantly increased levels of amyloid β1-42; tau protein; malondialdehyde; nuclear factor kappa-B; acetylcholinesterase activity, β-site amyloid precursor protein cleaving enzyme 1 upregulation and miRNA-124 downregulation. The best results of treatment were observed in the combination of donepezil and quercetin, as revealed by histopathological observations via H&E and Congo red stains. This study led to the conclusion that quercetin, by targeting several pathogenic pathways, could be used as an adjuvant drug with donepezil for AD treatment.},
}

Animals
*Quercetin/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced
Male
Rats
*MicroRNAs/metabolism
*Aspartic Acid Endopeptidases/metabolism
Disease Models, Animal
*Amyloid Precursor Protein Secretases/metabolism
Rats, Wistar
*Neurons/metabolism/pathology/drug effects
Donepezil/pharmacology
Hippocampus/metabolism/drug effects/pathology
*Neuroprotective Agents/pharmacology

@article {pmid40341601,
year = {2025},
author = {Kamat, PK and Kalani, A and Debnath, N and Mushtaq, Z and Tyagi, SC and Tyagi, N},
title = {Neuroprotective mechanism of hydrogen sulfide in okadaic acid-induced alzheimer-like pathology.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40341601},
issn = {2509-2723},
support = {971566//American Heart Association/ ; 24TPA1304527//American Heart Association/ ; },
abstract = {Okadaic acid (OKA) is a marine biotoxin that accumulates in shellfish and is responsible for causing diarrheic shellfish poisoning. OKA is a powerful and selective inhibitor of serine/threonine phosphatases 1 and 2A, which induces hyperphosphorylation of tau in vitro and in vivo leading to Alzheimer's disease (AD)-like pathology and memory impairment. Hydrogen sulfide (H2S), a gaseous signaling molecule produced endogenously in the brain, has been demonstrated to possess neuroprotective properties in various models of neurodegeneration. The aim of this study was to investigate the potential of H2S in reducing OKA-induced Alzheimer's disease (AD)-like pathology, focusing on its effects on the GSK3β/Tau and CaMKII/CREB signaling pathways in mice. To test this hypothesis, we used age 8-10 weeks-old male C57BL/6J wild-type mice, divided into the following experimental groups: 1. Control group: Received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF). 2. WT + OKA group: Received a single ICV injection of OKA (100 ng/5 µl) bilaterally to induce AD-like pathology. OKA was dissolved in artificial cerebrospinal fluid. 3. WT + OKA + GYY4137 group: Received a single ICV injection of OKA (100 ng/5 µl) bilaterally, followed by GYY4137 (30 µM/kg) via drinking water for 21 days. 4. WT + GYY4137 group: Received only GYY4137 per se (30 µM/kg) via drinking water for 21 days. After the treatment period, synaptic proteins and neurodegeneration were evaluated using Western blotting, RT-PCR, and immunohistochemistry techniques. Our results demonstrate that OKA administration results in memory impairment with decreased cerebral blood flow (CBF). OKA also caused a significant decrease in synapse proteins (PSD95, MAP-2, BDNF, CaMKIIα, and Tubulin-3β) levels, along with increased expression of Tau, PHF-1, and GSK-3β and memory-associated signaling molecules and pCREB. Interestingly, IP administration of GYY4137 (30 µM/Kg; an H2S donor) for 21 days significantly improved the level of synapse proteins and memory function in OKA-treated mice. The findings of this study determine the neuroprotective mechanism of H2S in OKA-induced AD-like pathology through the modulation of Tau, GSK3β, and pCREB signaling. Therefore, H2S ameliorates OKA-induced memory impairment by improving synapse function and forgetfulness. As a result, H2S could be used as a promising therapeutic molecule against Alzheimer's disease-like pathology.},
}

@article {pmid40341391,
year = {2025},
author = {Tabbal, J and Ebadi, A and Mheich, A and Kabbara, A and Güntekin, B and Yener, G and Paban, V and Gschwandtner, U and Fuhr, P and Verin, M and Babiloni, C and Allouch, S and Hassan, M},
title = {Characterizing the heterogeneity of neurodegenerative diseases through EEG normative modeling.},
journal = {NPJ Parkinson's disease},
volume = {11},
number = {1},
pages = {117},
pmid = {40341391},
issn = {2373-8057},
abstract = {Neurodegenerative diseases like Parkinson's (PD) and Alzheimer's (AD) exhibit considerable heterogeneity of functional brain features within patients, complicating diagnosis and treatment. Here, we use electroencephalography (EEG) and normative modeling to investigate neurophysiological mechanisms underpinning this heterogeneity. Resting-state EEG data from 14 clinical units included healthy adults (n = 499) and patients with PD (n = 237) and AD (n = 197), aged over 40. Spectral and source connectivity analyses provided features for normative modeling, revealing significant, frequency-dependent EEG deviations with high heterogeneity in PD and AD. Around 30% of patients exhibited spectral deviations, while ~80% showed functional source connectivity deviations. Notably, the spatial overlap of deviant features did not exceed 60% for spectral and 25% for connectivity analysis. Furthermore, patient-specific deviations correlated with clinical measures, with greater deviations linked to worse UPDRS for PD (⍴ = 0.24, p = 0.025) and MMSE for AD (⍴ = -0.26, p = 0.01). These results suggest that EEG deviations could enrich individualized clinical assessment in Precision Neurology.},
}

@article {pmid40341320,
year = {2025},
author = {Pickard, BS},
title = {A mechanism of global gene expression regulation is disrupted by multiple disease states and drug treatments.},
journal = {PloS one},
volume = {20},
number = {5},
pages = {e0317071},
doi = {10.1371/journal.pone.0317071},
pmid = {40341320},
issn = {1932-6203},
mesh = {Humans ; *Gene Expression Regulation/drug effects ; RNA, Messenger/genetics/metabolism ; Transcriptome ; Animals ; Gene Expression Profiling ; },
abstract = {Conventional expression studies quantify messenger RNA (mRNA) transcript levels gene-by-gene. We recently showed that protein expression is modulated at a global scale by amino acid availability, suggesting that mRNA expression levels might be equivalently affected. Through re-analysis of public transcriptomic datasets, it was confirmed that nucleobase supply interacts with the specific demands of mRNA A + U:C + G sequence composition to shape a global profile of expression, which can be quantified as a gradient of average expression change by average composition change. In mammals, each separate organ and cell-type displays a distinct baseline profile of global expression. These profiles can shift dynamically across the circadian day and the menstrual cycle. They are also significantly distorted by viral infection, multiple complex genetic disorders (including Alzheimer's disease, schizophrenia, and autoimmune disorders), and after treatment with 115 of the 597 chemical entities analysed. These included known toxins and nucleobase analogues, but also many commonly prescribed medications such as antibiotics and proton pump inhibitors, thus revealing a new mechanism of drug action and side-effect. As well as key roles in disease susceptibility, mRNAs with extreme compositions are significantly over-represented in gene ontologies such as transcription and cell division, making these processes particularly sensitive to swings in global expression. This may permit efficient, en bloc transcriptional reprogramming of cell state through simple adjustment of nucleobase proportion and supply. It is also proposed that this mechanism helped mitigate the loss of essential amino acid synthesis in higher organisms. In summary, global expression regulation is invisible to conventional transcriptomic analysis, but its measurement allows a useful distinction between active, promoter-mediated gene expression changes and passive, cell state-dependent transcriptional competence. Linking cell metabolism directly to gene expression offers an entirely new perspective on evolution, disease aetiopathology (including gene x environment - GxE - interactions), and the nature of the pharmacological response.},
}

Humans
*Gene Expression Regulation/drug effects
RNA, Messenger/genetics/metabolism
Transcriptome
Animals
Gene Expression Profiling

@article {pmid40340504,
year = {2025},
author = {Du, L and Sun, Y and Gan, Y and Wang, L and Li, X and Yan, S and Xiao, X and Li, S and Jin, H},
title = {Study on the mechanism of Xanthoceras sorbifolia Bunge oil in the treatment of Alzheimer's disease by an integrated "network pharmacology-metabolomics" strategy.},
journal = {Annals of medicine},
volume = {57},
number = {1},
pages = {2499700},
doi = {10.1080/07853890.2025.2499700},
pmid = {40340504},
issn = {1365-2060},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Network Pharmacology/methods ; Animals ; *Sapindaceae/chemistry ; Rats ; Metabolomics/methods ; Humans ; *Plant Oils/pharmacology/therapeutic use/chemistry ; Male ; Disease Models, Animal ; Rats, Sprague-Dawley ; Gas Chromatography-Mass Spectrometry ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Xanthoceras sorbifolia Bunge oil (XSBO) has garnered significant interest from researchers due to its distinctive anti-Alzheimer's disease (AD) properties. However, the underlying molecular mechanism remain unclear. This study aims to investigate the potential mechanisms by which XSBO may exert therapeutic effects on AD by employing a combination of network pharmacology analysis and experimental validation.

METHODS: The chemical composition and absorbed compounds of XSBO were identified using GC-MS and LC-MS. Network pharmacology analysis was performed using various computational tools to identify hub genes and construct compound-target-pathway networks. Subsequently, both in vitro and in vivo experiments were conducted to confirm the mechanisms by which XSBO may treat AD.

RESULTS: The results identified 43 active compounds in XSBO, targeting a total of 223 genes, of which 191 were associated with AD. Network analysis indicated that the active constituents in XSBO, such as 9,12-octadecadienoic acid, linoelaidic acid and 11-octadecenoic acid, interact with targets including MAPK1, MAPK3, AKT1, RXRA, RXRB, PPARD and PPARA to modulate inflammation-related signalling pathways and the sphingolipid signalling pathway. In vitro investigations corroborated that XSBO can significantly influence the viability of Aβ25-35-induced SH-SY5Y cells via the MAPK pathway.

CONCLUSIONS: This study demonstrated that XSBO has the potential to mitigate inflammation network disorders through the MAPK pathway and to restore sphingolipid metabolite levels in AD rats, thereby laying a groundwork for future studies.},
}

*Alzheimer Disease/drug therapy/metabolism
Network Pharmacology/methods
Animals
*Sapindaceae/chemistry
Rats
Metabolomics/methods
Humans
*Plant Oils/pharmacology/therapeutic use/chemistry
Male
Disease Models, Animal
Rats, Sprague-Dawley
Gas Chromatography-Mass Spectrometry
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid40340434,
year = {2025},
author = {Spangler, J and Skidmore, E and Dressler, EV and Weaver, KE and Lesser, GJ and Burton, G and Esparaz, B and Gillett, B and Shaw, EG},
title = {Randomized Placebo-Controlled Trial of Memantine for Smoking Cessation (CCCWFU 99311).},
journal = {Cancer control : journal of the Moffitt Cancer Center},
volume = {32},
number = {},
pages = {10732748251336416},
doi = {10.1177/10732748251336416},
pmid = {40340434},
issn = {1526-2359},
mesh = {Humans ; *Memantine/therapeutic use ; Male ; *Smoking Cessation/methods ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Tobacco Use Disorder/drug therapy ; Treatment Outcome ; },
abstract = {IntroductionQuitting smoking is challenging even with existing pharmacotherapy. Thus, discovery of new cessation medications is imperative. Memantine, a well-tolerated Alzheimer's disease drug, partially antagonizes glutamate at the N-methyl-D-Aspartate receptor (NMDAR), modulating dopamine release in addiction pathways. Memantine may interrupt nicotine reward and promote smoking cessation.Materials and MethodsAt 23 community oncology practices nationwide, we recruited 130 breast, prostate, lung, or colorectal cancer survivors ≥ six months beyond definitive treatment who currently smoked at least 10 cigarettes daily and wanted to quit. In a double-blind fashion, participants were randomized to take either memantine (10 mg) or a matching placebo twice daily for 12 weeks (65 per arm). Toxicity, nicotine dependence, and past-week abstinence were recorded at 2, 4-, 6-, 9-, and 12-weeks post-randomization. The primary endpoint was feasibility and preliminary estimation of 12-week self-reported past-week smoking abstinence.ResultsThere were no significant differences in abstinence rates or nicotine dependence between the two groups at 12 weeks. Twelve-week completion of therapy was low, but lower in memantine than control participants (42% vs 63%, respectively; P = .01). Memantine participants reported trends of less anxiety, craving, and hunger. No significant differences in toxicity were observed between groups. Serious adverse events (3 in memantine arm, 1 in control arm) occurred; none considered possibly or probably related to study medication.ConclusionMemantine did not improve 12-week smoking abstinence rates in cancer survivors. While other NMDAR antagonists might deserve evaluation, this study suggests memantine is not efficacious for smoking cessation in a cancer survivor subpopulation.Trial registration numberNCT01535040 - February 17, 2012.},
}

Humans
*Memantine/therapeutic use
Male
*Smoking Cessation/methods
Female
Middle Aged
Double-Blind Method
Aged
Tobacco Use Disorder/drug therapy
Treatment Outcome

@article {pmid40340356,
year = {2025},
author = {Roy, A and Roy, R and Bhattacharya, P and Borah, A},
title = {The Vicious Consequences of Chronic Kidney Disease on Cognitive Impairment and Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00050},
pmid = {40340356},
issn = {1948-7193},
abstract = {Chronic kidney disease (CKD) and Alzheimer's disease (AD) are two prevalent and debilitating conditions that frequently coexist, with CKD contributing to cognitive decline and potentially exacerbating AD pathology. In CKD, irreversible changes in the structure or function of the kidneys are observed, while AD is primarily marked by amyloid deposition and tau pathology. Both conditions involve complex and multifactorial pathophysiology affecting brain functioning, highlighting the need for comprehensive research to understand their potential crosstalk. This review articulates the possible molecular mechanisms underlying both diseases, focusing on key pathways, including oxidative stress, inflammation, vascular dysfunction, hypertension, and uremic toxin accumulation. These interconnected mechanisms suggest a potential bidirectional relationship where kidney dysfunction accelerates cognitive decline and vice versa. Additionally, we examine critical risk factors implicated in both CKD and AD, for instance, vitamin D deficiency, erythropoietin dysregulation, endothelin action, klotho gene expression, and the role of the extracellular vesicle, which may influence disease progression through their effects on the kidney and brain, influencing cognitive function. Further, we emphasized potential biomarkers that could aid in diagnosing and monitoring disease progression in these comorbid conditions, like amyloid beta, tau, homocysteine, cystatin C, creatinine, proteinuria, and estimated glomerular filtration rate. Lastly, the review highlights treatment strategies for managing CKD and AD concurrently, focusing on therapeutic approaches that address common pathophysiological mechanisms. These strategies not only aim to address the underlying causes of both conditions but also offer the potential to slow or even prevent the progression of cognitive impairment. Moreover, we recommend further research to refine these approaches, execute correlational studies on disease progression, and design clinical trials that address both conditions, aiming to establish effective, tailored treatments for this dual burden of disease.},
}

@article {pmid40340118,
year = {2025},
author = {Wu, Q and Huang, C and Zhang, J and Zhang, Z and Zhu, X},
title = {Artificial Intelligence-Assisted Hippocampal Segmentation and Its Diagnostic Value for Alzheimer's Disease: A Meta-analysis.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2025.04.038},
pmid = {40340118},
issn = {1878-4046},
abstract = {BACKGROUND: Hippocampal atrophy is a key marker of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Diverse artificial intelligence (AI) architectures for automated hippocampal segmentation have been increasingly reported in neuroimaging research. Different hippocampal automated segmentation methods can be of added value for the AD diagnostic work-up and treatment planning. This study aims to conduct a thorough meta-analysis to evaluate the segmentation accuracy and diagnostic performance of AI-assisted hippocampal segmentation in AD and MCI.

METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library up to December 2024. Studies using neuroimaging data to assess AI algorithms for hippocampal segmentation and diagnosis in AD or MCI populations were included. Pooled segmentation accuracy was estimated using the Dice similarity coefficient (DSC) through a random-effects model, while diagnostic performance (sensitivity, specificity, and area under the curve [AUC]) was evaluated using a bivariate mixed-effects model.

RESULTS: A total of 27 studies were included. For segmentation accuracy, pooled DSC values were 0.82 (95% CI: 0.80-0.85) for AD, 0.85 (0.83-0.88) for MCI, and 0.86 (0.84-0.88) for normal controls (NC). Subgroup analyses indicated comparable performance between left and right hippocampi (both DSC: 0.87). Diagnostic meta-analysis demonstrated the highest accuracy for AD vs. NC (sensitivity: 0.87, specificity: 0.91, AUC: 0.95), but lower performance for AD vs. MCI (AUC: 0.80) and MCI vs. NC (AUC: 0.83).

CONCLUSION: AI-assisted hippocampal segmentation achieves good accuracy and demonstrates promising diagnostic capabilities for distinguishing AD from NC, though differentiation between AD and MCI remains challenging. Future high-quality research that applied standardized protocols, external validation, and clinical integration is needed to improve reliability in clinical practice.},
}

@article {pmid40340068,
year = {2025},
author = {Cuello, AC},
title = {The involvement of the cholinergic system in Alzheimer disease.},
journal = {Handbook of clinical neurology},
volume = {211},
number = {},
pages = {63-79},
doi = {10.1016/B978-0-443-19088-9.00005-6},
pmid = {40340068},
issn = {0072-9752},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Animals ; *Acetylcholine/metabolism ; Cholinesterase Inhibitors/therapeutic use ; *Brain/metabolism/pathology ; },
abstract = {This chapter recounts how memory mechanisms were related to the CNS cholinergic system. It also examines how memory loss in aging individuals was later linked to cholinergic deficiencies and how extensive pharmacologic studies in primates led to the "Cholinergic Hypothesis" of geriatric memory loss. Building upon this, a series of influential publications revealed a loss of cholinergic markers in the cerebral cortex of postmortem Alzheimer disease brain samples. These studies were reinforced by histologic evidence of the degeneration of "magnocellular" neurons in the nucleus basalis of Meynert, the region where neurons that project cortical cholinergic synaptic terminals originate. Together, these discoveries gave rise to the so-called Cholinergic hypothesis of Alzheimer disease. This chapter further describes how these insights prompted the development of potential cholinergic therapies, initially involving acetylcholine precursors, followed by the introduction of anticholinesterase inhibitors. This progression began with Tacrine and eventually led to the development of more reliable and better-tolerated anticholinesterases, such as donepezil, rivastigmine, and galantamine-compounds still in use today. The narrative includes a discussion of the benefits and limitations of these drugs, as well as the potential of newly developed muscarinic and nicotinic agonists. The chapter concludes with a brief overview of the synaptic nature of cholinergic transmission, in contrast to the proposed "cloud" neurotransmission. It also emphasizes that the efficacy of anticholinesterase treatment in Alzheimer disease depends on the preservation of a minimal number of remaining cholinergic synapses. Finally, a comparison is made between the symptomatic cognitive outcomes of conventional anticholinesterase therapy and the more recent use of anti-amyloid monoclonal antibodies.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
Animals
*Acetylcholine/metabolism
Cholinesterase Inhibitors/therapeutic use
*Brain/metabolism/pathology

@article {pmid40340063,
year = {2025},
author = {Soreq, H and Bar, A and Paldor, I},
title = {The cholinergic synapses.},
journal = {Handbook of clinical neurology},
volume = {211},
number = {},
pages = {23-35},
doi = {10.1016/B978-0-443-19088-9.00003-2},
pmid = {40340063},
issn = {0072-9752},
mesh = {Humans ; Animals ; *Synapses/metabolism/physiology ; *Acetylcholine/metabolism ; *Cholinergic Neurons/physiology ; },
abstract = {Acetylcholine (ACh) is a leading regulatory neurotransmitter in the nervous system, which functions both directly and as modulator of other neurotransmitters. It is found in the central and peripheral nervous system, as well as in the autonomic system-both sympathetic and parasympathetic. In the central nervous system (CNS), ACh functions not only as a neurotransmitter, but also as a modulator of cognitive functions, including long-term and short-term memory, limbic activation, and alertness. No process in the mammalian body can commence without its participation.},
}

Humans
Animals
*Synapses/metabolism/physiology
*Acetylcholine/metabolism
*Cholinergic Neurons/physiology

@article {pmid40340060,
year = {2025},
author = {Fisher, A and Levey, AI},
title = {CNS muscarinic receptors and muscarinic receptor agonists in Alzheimer disease treatment.},
journal = {Handbook of clinical neurology},
volume = {211},
number = {},
pages = {161-184},
doi = {10.1016/B978-0-443-19088-9.00016-0},
pmid = {40340060},
issn = {0072-9752},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Muscarinic Agonists/therapeutic use/pharmacology ; *Receptors, Muscarinic/metabolism ; Animals ; Receptor, Muscarinic M1 ; },
abstract = {This review explores the main aspects that form the basis of the cholinergic-oriented treatment of Alzheimer disease. Muscarinic acetylcholine receptor subtypes in the brain and periphery are discussed. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer disease and the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. Activation of the M1 muscarinic receptor is a rational therapeutic strategy for the treatment of schizophrenia and Alzheimer disease, as this receptor plays a pivotal role in modulating cognitive deficits and the pathology of the disease. Such activation can be achieved through M1 allosteric and bitopic muscarinic agonists, M1 positive allosteric modulators (M1 PAMs), and direct-acting M1 muscarinic orthosteric agonists. The efficacy of M1 PAMs depends on acetylcholine, which declines in Alzheimer disease as postsynaptic neurons lose cholinergic input from the basal forebrain. On the other hand, the activity of M1 muscarinic orthosteric agonists is independent of the functional or anatomic integrity of presynaptic cholinergic terminals, and likely retain efficacy as the disease progresses, even after presynaptic degeneration of cholinergic fibers. Based on the acceptance criteria for a preferred M1 muscarinic agonist for the treatment of AD, aiming for efficacy, specificity, and safety in clinical use, few M1 muscarinic agonists fulfill these requirements, such as orthosteric M1 agonists-cevimeline (aka AF102B), the first FDA-approved M1 agonist, and NSC001 (aka AF267B). The pros and cons of various muscarinic agonists developed are critically discussed in comparison to these drugs. The review proposes new alternatives to cholinergic therapy, particularly selective M1 muscarinic drugs, that should be designed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Muscarinic Agonists/therapeutic use/pharmacology
*Receptors, Muscarinic/metabolism
Animals
Receptor, Muscarinic M1

@article {pmid40340059,
year = {2025},
author = {Gauthier, S and Therriault, J and Rosa-Neto, P},
title = {Cholinergic therapy in Alzheimer disease.},
journal = {Handbook of clinical neurology},
volume = {211},
number = {},
pages = {155-159},
doi = {10.1016/B978-0-443-19088-9.00015-9},
pmid = {40340059},
issn = {0072-9752},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/therapeutic use ; *Cholinergic Agents/therapeutic use ; },
abstract = {This chapter describes how the clinical efficacy of orally administered cholinesterase inhibitors has been demonstrated through placebo-controlled randomized clinical trials leading to regulatory approval worldwide for the symptomatic treatment of Alzheimer disease. Over time, other clinical indications have been found, such as Dementia with Lewy Bodies and Parkinson disease Dementia. The route of administration includes transdermal patches. Side effects predominantly arise from peripheral parasympathetic stimulation. There is hope that drugs acting on acetylcholine release or on muscarinic receptors can exert additional symptomatic benefits.},
}

Humans
*Alzheimer Disease/drug therapy
*Cholinesterase Inhibitors/therapeutic use
*Cholinergic Agents/therapeutic use

@article {pmid40340058,
year = {2025},
author = {Boccalini, C and Perani, D and Garibotto, V},
title = {Memory network and cognitive reserve are associated with preserved and stimulated cholinergic neurotransmission.},
journal = {Handbook of clinical neurology},
volume = {211},
number = {},
pages = {137-153},
doi = {10.1016/B978-0-443-19088-9.00014-7},
pmid = {40340058},
issn = {0072-9752},
mesh = {Humans ; *Cognitive Reserve/physiology ; *Synaptic Transmission/physiology ; *Memory/physiology ; Animals ; *Cholinergic Neurons/physiology ; *Brain/metabolism ; },
abstract = {The cholinergic system plays a central role in cognition and neural function, and, in Alzheimer disease (AD) and Lewy body disease (LBD), it has profound implications for cognitive impairment and dementia. The cholinergic forebrain pathway, innervating the neocortex and limbic system, is crucial for learning, memory, and other essential aspects of cognition and plays a wider role in promoting neuronal plasticity. Given the neuroplasticity processes characterizing the cholinergic regions, this system may be sensitive to modulatory phenomena such as cognitive reserve (CR). The concept of CR has been introduced to account for the fact that individual clinical presentation might be milder than expected based on neuropathology. This mismatch can be explained by individual brain reserve (BR) buildup on life experiences, lifestyles, and neurobiologic factors that are associated with resilience. Sparse findings exist suggesting that the CR might result in an increased or preserved function of the cholinergic system in AD patients, and compensatory mechanisms in the early stages of LBD. The limited availability of effective treatment for neurodegenerative dementia emphasizes the importance of CR and BR, as they play a major role in delaying or slowing disease onset and progression. This chapter will describe the involvement of the cholinergic system in neurodegenerative diseases and the tools for the in vivo assessment, focusing specifically on the evidence suggesting the possibility of its modulation by CR.},
}

Humans
*Cognitive Reserve/physiology
*Synaptic Transmission/physiology
*Memory/physiology
Animals
*Cholinergic Neurons/physiology
*Brain/metabolism

@article {pmid40340057,
year = {2025},
author = {Mitra, S and Gera, R and Eriksdotter, M},
title = {NGF-based cholinergic therapies in Alzheimer disease.},
journal = {Handbook of clinical neurology},
volume = {211},
number = {},
pages = {123-135},
doi = {10.1016/B978-0-443-19088-9.00007-X},
pmid = {40340057},
issn = {0072-9752},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Nerve Growth Factor/metabolism/therapeutic use ; Animals ; *Cholinesterase Inhibitors/therapeutic use ; *Cholinergic Agents/therapeutic use ; Acetylcholine/metabolism ; Cholinergic Neurons/drug effects ; },
abstract = {The cholinergic system is part of the parasympathetic nervous system, which works in tandem with the sympathetic and enteric nervous systems to maintain the physiologic functioning of our body. The neurotransmitter acetylcholine (ACh) facilitates cholinergic signaling pathways by activating specific cell surface receptors (nicotinic and muscarinic receptors). Altered cholinergic signaling has been implicated in several pathologic conditions. In this chapter, conditions where cholinergic modulation in the central nervous system occurs through the neurotrophin nerve growth factor (NGF) are addressed. NGF is the master regulator of several pathways, ultimately leading to cell survival, ACh production, regenerative signaling, and anti-inflammatory tone. NGF and cholinergic-related pathways have been reported to be severely affected in the case of Alzheimer disease (AD), the most common dementia disorder. In AD, the cholinergic nuclei of the basal forebrain are affected early during the AD continuum, resulting in cholinergic cell loss and hampered ACh production, which overall affects the propagation of cholinergic signals in other brain regions. Since the 1990s clinically relevant strategies to treat AD patients have been the drugs that enhance cholinergic signaling-termed cholinesterase inhibitors (ChEIs), however, other strategies in AD have been and are presently being assessed for clinical efficacy. Delivery of NGF to the basal forebrain is considered crucial to revive the cholinergic cell bodies, restore ACh production, and sustain cognitive function. This chapter provides a description of the relevance of NGF-based therapies targeted for AD treatment, technical approaches for NGF delivery to the brain, and the status of ongoing clinical studies are provided.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Nerve Growth Factor/metabolism/therapeutic use
Animals
*Cholinesterase Inhibitors/therapeutic use
*Cholinergic Agents/therapeutic use
Acetylcholine/metabolism
Cholinergic Neurons/drug effects

@article {pmid40340000,
year = {2025},
author = {Bhati, V and Prasad, S and Kabra, A},
title = {RNA-based therapies for neurodegenerative disease: Targeting molecular mechanisms for disease modification.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104010},
doi = {10.1016/j.mcn.2025.104010},
pmid = {40340000},
issn = {1095-9327},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal damage, protein aggregation, and chronic inflammation, leading to cognitive and motor impairments. Despite symptomatic relief from current therapies, disease-modifying treatments targeting the core molecular mechanism are still lacking. RNA-based therapies offer a promising approach to treating neurodegenerative disease by targeting molecular mechanisms such as gene expression, protein synthesis, and neuroinflammation. Therapeutic strategies include Long non-coding RNA (lncRNA), Antisense oligonucleotides (ASOs), RNA interference (RNAi), small interfering RNA (siRNA) and short hairpin RNA (shRNA), messenger RNA (mRNA) therapies, and microRNA (miRNA)-based interventions. These therapies aim to decrease toxic protein accumulation, restore deficient proteins, and modulate inflammatory responses in conditions like AD, PD, and HD. Unlike conventional treatments that primarily manage symptoms, RNA-based therapies have the potential to modify disease progression by addressing its root causes. This review aims to provide a comprehensive overview of current RNA-based therapeutic strategies for neurodegenerative diseases, discussing their mechanism of action, preclinical and clinical advancement. It further explores innovative solutions, including nanocarrier-mediated delivery, chemical modifications to enhance RNA stability, and personalized medicine approaches guided by genetic profiling that are being developed to overcome these barriers. This review also underscores the therapeutic opportunities and current limitations of RNA-based interventions, highlighting their potential to transform the future of neurodegenerative disease management.},
}

@article {pmid40339911,
year = {2025},
author = {Villavicencio-Tejo, F and Olesen, MA and Ampuero, E and Quintanilla, RA},
title = {Sulforaphane prevents cognitive decline and mitochondrial failure induced by hippocampal expression of caspase-3 cleaved tau.},
journal = {Neurochemistry international},
volume = {187},
number = {},
pages = {105991},
doi = {10.1016/j.neuint.2025.105991},
pmid = {40339911},
issn = {1872-9754},
abstract = {Caspase-3 cleaved tau (truncated tau) is a pathological modification in tau protein that contributes to neurofibrillary tangle formation (NFTs) and neurodegeneration in AD. Our previous studies indicate that truncated tau affects mitochondrial health, synaptic plasticity, and cognitive performance. Therefore, we studied the effects of sulforaphane (SFN), a natural compound activator of the NRF2 antioxidant pathway present in vegetables and sprouts, on neurodegeneration and cognitive decline induced by truncated tau expression in vivo. We induced a 2-month hippocampal expression of GFP, full-length (AAV-Syn-GFP-T4) and truncated tau (AAV-Syn-GFP-T4C3) using a stereotaxic injection of adeno-associated-virus-9 (AAV9) linked to GFP and a synapsin neuronal promoter in tau (-/-) mice. Hippocampal tau-expressing mice were treated with SFN, and their cognitive performance (NOR, NOL, and Barnes maze tests) and hippocampal mitochondrial function were analyzed. Interestingly, hippocampal truncated tau expression significantly affected cognitive and memory abilities, accompanied by increased ROS and severe mitochondrial dysfunction (depolarization, ATP loss, dynamics de-regulation). Notably, the treatment with SFN (50 mg/kg/day, i.p., two weeks) prevented cognitive impairment and reduced mitochondrial bioenergetics and dynamics defects induced by hippocampal truncated tau expression. These findings suggest a potential role of SFN in ameliorating cognitive loss and mitochondrial impairment promoted by tau pathology in neurological disorders (NDs).},
}

@article {pmid40339619,
year = {2025},
author = {Zare, MS and Abedpoor, N and Hajibabaie, F and Walker, AK},
title = {Gene co-expression patterns shared between chemobrain and neurodegenerative disease models in rodents.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106944},
doi = {10.1016/j.nbd.2025.106944},
pmid = {40339619},
issn = {1095-953X},
abstract = {Chemotherapy-related cognitive impairment (CRCI), is a well-recognized phenomenon in cancer patients who have undergone chemotherapy but the exact molecular mechanisms underpinning CRCI remain elusive. Symptoms reported by patients with CRCI resemble those experienced by patients with age-related neurodegenerative disorders (ARNDDs), yet no clear connection between CRCI and ARNDDs has been reported to date. The existence of shared mechanisms between these conditions offers opportunities for repurposing drugs already approved for the treatment of ARNDDs to improve symptoms of CRCI. Given that there is no available microarray or RNA-Seq data from the brains of patients who have experienced CRCI, we investigated to what extent brain gene expression perturbations from validated rodent models of CRCI induced by chemotherapy compared with validated rodent models of Alzheimer's disease and Parkinson's disease. We utilized multiple bioinformatic analyses, including functional enrichment, protein-protein interaction network analyses, gene ontology analyses and identification of hub genes to reveal connections between comparable gene expression perturbations observed in these conditions. Collectively 165 genes overlapped between CRCI and Parkinson's disease and/or Alzheimer's disease, and 15 overlapped between all three conditions. The joint genes between Alzheimer's disease, Parkinson's disease and CRCI demonstrate an average of 83.65% nucleotide sequence similarity to human orthologues. Gene ontology and pathway enrichment analyses suggest mechanisms involved in neural activity and inflammatory response as the key components of the studied neuropathological conditions. Accordingly, genes in which expression was comparably affected in all three condition models could be attributed to neuroinflammation, cell cycle arrest, and changes in physiological neural activity.},
}

@article {pmid40339155,
year = {2025},
author = {Chen, XQ and Zuo, X and Becker, A and Mante, M and Florio, JB and Jadhav, SG and Albay, R and Johnstone, A and Karachentsev, D and Rissman, R and Zhao, H and Dowdy, SF and Mobley, WC},
title = {Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70022},
doi = {10.1002/alz.70022},
pmid = {40339155},
issn = {1552-5279},
support = {R-86U55A//DH Chen Foundation/ ; R01AG061151/NH/NIH HHS/United States ; R01AG055523/NH/NIH HHS/United States ; R01AG070154/NH/NIH HHS/United States ; UCSD2019-2544//Cure Alzheimer's Fund/ ; },
mesh = {Animals ; *Oligonucleotides, Antisense/pharmacology ; *rab5 GTP-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; *Down Syndrome/metabolism/genetics/pathology ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Endosomes/metabolism ; *rab GTP-Binding Proteins/metabolism ; *Alzheimer Disease/metabolism/genetics/pathology ; Mice, Transgenic ; Phenotype ; Brain/metabolism/pathology ; Humans ; },
abstract = {INTRODUCTION: Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS-AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11.

METHODS: We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS-AD mouse model was treated with a mouse App-specific antisense oligonucleotide (App-ASO) and Rab5-specific ASOs targeting Rab5a and Rab5b.

RESULTS: App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5-ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS-AD-linked pathologies.

DISCUSSION: These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features.

HIGHLIGHTS: App-ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5-ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP-linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App-ASO or Rab5-ASOs reversed established pathological phenotypes in Dp16 mice.},
}

Animals
*Oligonucleotides, Antisense/pharmacology
*rab5 GTP-Binding Proteins/metabolism/genetics
Disease Models, Animal
Mice
*Down Syndrome/metabolism/genetics/pathology
*Amyloid beta-Protein Precursor/genetics/metabolism
*Endosomes/metabolism
*rab GTP-Binding Proteins/metabolism
*Alzheimer Disease/metabolism/genetics/pathology
Mice, Transgenic
Phenotype
Brain/metabolism/pathology
Humans

@article {pmid40338826,
year = {2025},
author = {, },
title = {Retraction: Structure-based virtual screening of Trachyspermum ammi metabolites targeting acetylcholinesterase for Alzheimer's disease treatment.},
journal = {PloS one},
volume = {20},
number = {5},
pages = {e0324094},
doi = {10.1371/journal.pone.0324094},
pmid = {40338826},
issn = {1932-6203},
}

@article {pmid40337272,
year = {2025},
author = {Fairburn, SC and Jehi, L and Bicknell, BT and Wilkes, BG and Panuganti, B},
title = {Applications of quantum computing in clinical care.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1573016},
pmid = {40337272},
issn = {2296-858X},
abstract = {INTRODUCTION: This review examines quantum computing (QC) applications in clinical care, emphasizing advancements directly impacting patient outcomes. QC holds transformative potential in medicine, particularly through enhancing diagnostic accuracy, optimizing treatment plans, and enabling real-time decision-making.

METHODS: A systematic analysis of 35 studies published between 2015 and 2024 was conducted. The studies were evaluated for their contributions to diagnostic, therapeutic, and decision-support improvements in clinical care enabled by quantum computing technologies.

RESULTS: The analysis revealed QC's promise in improving diagnostic accuracy in medical imaging, optimizing treatments in oncology, and enhancing real-time clinical decision-making. QC-driven algorithms demonstrated potential to enhance diagnostic accuracy and computational efficiency. These improvements could enable earlier detection of diseases such as Alzheimer's, cancer, and osteoarthritis, supporting more timely interventions and better prognoses.

DISCUSSION: Despite promising outcomes, current limitations-such as hardware scalability, error mitigation, and ethical considerations-hinder widespread adoption of QC in clinical settings. Overcoming these challenges will require interdisciplinary collaboration and technological innovation. The review underscores QC's capacity to deliver precise, personalized, and efficient care, advocating for its integration into healthcare workflows to advance precision medicine and improve patient outcomes.},
}

@article {pmid40337158,
year = {2025},
author = {Sabbagh, M and Boschini, C and Cohen, S and Fugger, M and Jessen, F and Dandanell, S and Pedersen, SD and Tarazona, LRS and Aroda, VR},
title = {Safety considerations of semaglutide in the potential treatment of Alzheimer's disease: A pooled analysis of semaglutide in adults aged ≥ 65 years.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70076},
pmid = {40337158},
issn = {2352-8737},
abstract = {INTRODUCTION: The evoke/evoke+ trials are investigating semaglutide in a population with early Alzheimer's disease (AD). Specific analyses of semaglutide safety data in older adults are limited; therefore, in the current analysis, we aimed to evaluate safety considerations with semaglutide in adults ≥ 65 years.

METHODS: Adverse event (AE) data from three semaglutide phase 3a programs in participants ≥ 65 years with type 2 diabetes and/or overweight/obesity were pooled. Change in body weight was also assessed in a smaller subset of participants ≥ 65 years.

RESULTS: The analysis included 3529 participants ≥ 65 years. Baseline mean age and body mass index in participants ≥ 65 years were 69.3 to 70.2 years and 29.7 to 35.4 kg/m[2], respectively, compared to 47.8 to 58.5 years and 31.3 to 36.7 kg/m[2] in the overall population. AEs with semaglutide occurred in 73.6% to 92.4% of participants ≥ 65 years versus 73.2% to 90.8% of the overall population. AEs with semaglutide leading to permanent discontinuation appeared to be more frequent in participants ≥ 65 years (9.3%-12.4%) versus the overall population (5.7%-8.7%). Gastrointestinal disorders were the most frequently reported AEs with semaglutide in participants ≥ 65 years (44.6%-73.8%) and in the overall population (39.1%-73.4%). Participants aged ≥ 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52 compared to 0.1% with placebo.

DISCUSSION: Age ≥ 65 years did not appear to affect the safety considerations of semaglutide. The ongoing evoke/evoke+ trials will elucidate the balance of efficacy and safety in the treatment of early AD with semaglutide.

HIGHLIGHTS: This was a post hoc analysis evaluating adverse event (AE) data of semaglutide in people ≥ 65 years.The most common AE with semaglutide was gastrointestinal (GI).GI event rates were similar in people ≥ 65 years and the overall study populations.},
}

@article {pmid40336947,
year = {2025},
author = {Tran, NB and Lee, H and Ji, MG and Ngo Hoang, L and Lee, SJ},
title = {The synergistic extract of Zophobas atratus and Tenebrio molitor regulates neuroplasticity and oxidative stress in a scopolamine-induced cognitive impairment model.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1566621},
pmid = {40336947},
issn = {1663-4365},
abstract = {INTRODUCTION: Neurodegenerative disorders, such as Alzheimer's disease, arise from neuroinflammation, which leads to cognitive and memory impairment. Scopolamine is commonly used to induce cognitive and memory deficits in mouse models.

AIMS: This study investigated the neuroprotective potential of a Zophobas atratus (Za) and Tenebrio molitor (Tm) extract mixture (ZaTm mixture) in mitigating scopolamine-induced cognitive and memory deficits in mice.

RESULTS: Behavioral assessments, including the Morris water maze, Y-maze, and light/dark tests, demonstrated that the ZaTm mixture significantly enhanced memory and cognitive function in treated mice. Furthermore, the ZaTm mixture restored the disrupted expression of choline acetyltransferase and acetylcholinesterase in the hippocampi of scopolamine-treated mice. Additionally, scopolamine-induced glutamatergic/GABAergic dysfunction was markedly improved following treatment with the ZaTm mixture. The extract also exhibited neuroprotective effects by enhancing the activity of antioxidants, such as glutathione and malondialdehyde, and key enzymes, including catalase and superoxide dismutase. Moreover, it effectively inhibited senescence in the hippocampus by modulating the AMPK/SIRT and BDNF-Akt/mTOR signaling pathways.

DISCUSSION: This study highlights the promising potential of the ZaTm extract mixture as a novel therapeutic agent and functional food for the prevention and treatment of Alzheimer's disease and other neurodegenerative disorders.},
}

@article {pmid40336945,
year = {2025},
author = {Zhang, Y and Dong, K and Yang, J and Guo, Q and Zhao, Y and Zhu, X and Liu, D and Liu, P},
title = {Comparative efficacy of rTMS on different targets in Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1536573},
pmid = {40336945},
issn = {1663-4365},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising non-invasive intervention for Alzheimer's disease (AD), yet therapeutic outcomes remain inconsistent across studies. This meta-analysis aimed to evaluate the cognitive benefits of rTMS in AD patients, with a specific focus on stimulation targets and protocols variations.

METHODS: A systematic literature search was conducted in PubMed, Web of Science, Embase, and Cochrane Library for relevant English-language studies published up to 31 May 2024. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-Cog). Data were pooled using a random-effects model, with standardized mean difference (SMD) or mean differences (MD) and 95% confidence intervals (CI) calculated. Subgroup analyses were performed to examine the effects of stimulation targets, protocol variations and population demographics on rTMS efficacy.

RESULTS: Twenty-two studies involving 874 participants were included in this meta-analysis. Overall, rTMS significantly improved cognitive function (SMD = 0.27; 95% CI = 0.14-0.41; p < 0.0001), showing that the efficacy of rTMS varied by stimulation target and protocol. Stimulation of the dorsolateral prefrontal cortex (DLPFC) led to significant cognitive improvement (SMD = 0.49, 95% CI = -0.26 to 0.73; p < 0.0001), whereas bilateral DLPFC stimulation showed no significant improvement (SMD = 0.13; 95% CI = -0.40 to 0.66; p = 0.62). Stimulating the parietal lobe or associated regions produced moderate cognitive benefits (SMD = 0.29; 95% CI = 0.03-0.55; p = 0.03). Notably, multi-target stimulation over the bilateral DLPFC, parietal lobes, Wernicke's area, and Broca's area also showed substantial cognitive improvement (MD = 2.85; 95% CI = 1.69-4.00; p < 0.00001). Additionally, subgroup analysis based on geographical background revealed greater effects in studies conducted in Asia (SMD = 0.40, 95% CI = 0.14-0.65; p < 0.003).

CONCLUSION: rTMS is an effective intervention for cognitive enhancement in AD, with its efficacy significantly influenced by stimulation target and protocol. Notably, the greater cognitive benefits observed in Asian populations suggest a potential role of genetic and demographic factors that warrant further investigation. These findings contribute to the development of optimized, personalized rTMS protocols for AD treatment.

https://www.crd.york.ac.uk/PROSPERO/recorddashboard, CRD42023434084.},
}

@article {pmid40335871,
year = {2025},
author = {Saha, C and Figley, CR and Lithgow, B and Wang, X and Fitzgerald, PB and Koski, L and Mansouri, B and Moussavi, Z},
title = {Using baseline MRI radiomic features to predict the efficacy of repetitive transcranial magnetic stimulation in Alzheimer's patients.},
journal = {Medical & biological engineering & computing},
volume = {},
number = {},
pages = {},
pmid = {40335871},
issn = {1741-0444},
support = {CT140075//Weston Brain Institute/ ; },
abstract = {The efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for Alzheimer's disease (AD) is uncertain at baseline. Herein, we aimed to investigate whether radiomic features from the pre-treatment MRI data could predict rTMS efficacy for AD treatment. Out of 110 participants with AD in the active (n = 75) and sham (n = 35) rTMS treatment groups having T1-weighted brain MRI data, we had two groups of responders (active = 55 and sham = 24) and non-responders (active = 20 and sham = 11). We extracted histogram-based radiomic features from MRI data using 3D Slicer software; the most important features were selected utilizing a combination of a two-sample t-test, correlation test, least absolute shrinkage, and selection operator. The support vector machine classified rTMS responders and non-responders with a cross-validated mean accuracy/AUC of 81.9%/90.0% in the active group and 87.4%/95.8% in the sham group. Further, the radiomic features of the active group significantly correlated with participants' AD assessment scale-cognitive subscale (ADAS-Cog) change after treatment (false discovery rate corrected p < 0.05). Given that baseline radiomic features were able to accurately predict AD patients' responses to rTMS treatment, these radiomic features warrant further investigation for personalizing AD therapeutic strategies.},
}

@article {pmid40335778,
year = {2025},
author = {Lin, J and Li, H and Jiang, L and Li, J},
title = {Novel strategies for targeting tau oligomers in neurodegenerative diseases.},
journal = {Journal of neurology},
volume = {272},
number = {6},
pages = {383},
pmid = {40335778},
issn = {1432-1459},
support = {Grant No.YX202206//the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University/ ; Grant No.W20243174//Health Research Project of Hunan Provincial Health Commission/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy ; Animals ; Neurofibrillary Tangles/metabolism/pathology ; },
abstract = {Tau protein is a soluble microtubule-associated protein enriched in neurons, is mainly distributed in the central nervous system, and is responsible for stabilizing neurons. Tau maintains nerve cell morphology and internal transport by binding to normal microtubules. In neurodegenerative diseases, such as Alzheimer's disease (AD), tau proteins undergo aberrant phosphorylation, resulting in their removal from microtubules and the formation of neurofibrillary tangles (NFTs), which are key pathological features. In contrast to the late formation of non-soluble NFTs, early, smaller, soluble tau oligomers (tauO) with disseminated toxicity are considered necessary in neurodegenerative disorders, such as the primary form of tau toxicity in the AD process. Although an increasing number of studies are focusing on tauO, there are still problems to be solved, mainly concerning the molecular and inhibitory mechanisms of tauO toxicity. In this paper, we summarize the new strategies for the molecular mechanisms of tauO toxicity, detection methods, and interventions in the last five years. An outlook on these new strategies and the challenges that may be foreseen is presented to provide new directions for future applications in the clinical treatment of neurodegenerative diseases.},
}

Humans
*tau Proteins/metabolism
*Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy
Animals
Neurofibrillary Tangles/metabolism/pathology

@article {pmid40335710,
year = {2025},
author = {She, LY and Li, LY and Tang, H and Yu, Q and Gao, FY and Zeng, YQ and Chen, LJ and Xiong, L and Li, LW and Chen, F and Sun, JF and Zheng, WH and Zhao, X and Liang, G},
title = {OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {40335710},
issn = {1745-7254},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Microglia-mediated neuroinflammation is closely associated with AD pathogenesis. Abnormal deubiquitinating enzyme (DUB) expression is associated with neuroinflammation. Identification of functional DUBs in microglia may provide novel targets for AD treatment. Here, we found that the levels of DUB, ovarian tumor deubiquitinase 1 (OTUD1), were upregulated in AD model mice and amyloid-beta-induced microglia. OTUD1 knockdown in microglia significantly inhibited neuroinflammation, thereby improving cognitive impairment in AD model mice. Liquid chromatography-tandem mass spectrometry analysis coupled with co-immunoprecipitation revealed the CCAAT/enhancer-binding protein β (C/EBPβ), a key transcription factor regulating microglial inflammation, as an OTUD1-interacting protein. Mechanistically, OTUD1 bound to C/EBPβ and maintained its stability by removing the K48 ubiquitin chain at K253 of C/EBPβ, thereby activating the C/EBPβ-nuclear factor-κB-mediated inflammatory responses in microglia. Overall, our results revealed the roles of the OTUD1-C/EBPβ axis in mediating the microglial inflammatory responses and AD pathology, facilitating the development of new strategies targeting microglial neuroinflammation for AD treatment.},
}

@article {pmid40335607,
year = {2025},
author = {Aloui, M and El Fadili, M and Mujwar, S and Er-Rajy, M and Abuelizz, HA and Er-Rahmani, S and Zarougui, S and Menana, E},
title = {In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {15910},
pmid = {40335607},
issn = {2045-2322},
support = {Project (No. RSPD2024R566)//King Saud University, Riyadh, Saudi Arabia./ ; },
mesh = {*Pyridazines/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Drug Design ; Amyloid beta-Peptides/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Quantitative Structure-Activity Relationship ; Animals ; Computer Simulation ; },
abstract = {Alzheimer's disease (AD) necessitates innovative therapeutic approaches that target its multifaceted pathology. This study investigates a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as potential multi-target ligands for AD, aiming to simultaneously inhibit acetylcholinesterase (AChE) and amyloid-beta (Aβ) aggregation. To assess the therapeutic potential of these compounds, we employed a comprehensive computational approach, incorporating 2D-QSAR modeling, molecular dynamics simulations, molecular docking, and ADMET property analysis. Based on these analyses, we designed 13 novel pyridazine derivatives exhibiting favorable interactions with key AD-related proteins, enhanced dynamic stability within protein binding sites, and adherence to established drug-likeness principles. Notably, these compounds demonstrated promising oral absorption (96%) and exhibited no significant toxicity in preliminary assessments. These results indicate that the novel pyridazine derivatives warrant further investigation as promising multifunctional agents for the treatment of Alzheimer's disease.},
}

*Pyridazines/chemistry/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
*Drug Design
Amyloid beta-Peptides/metabolism/chemistry
Acetylcholinesterase/metabolism/chemistry
*Cholinesterase Inhibitors/chemistry/pharmacology
Quantitative Structure-Activity Relationship
Animals
Computer Simulation

@article {pmid40334809,
year = {2025},
author = {Liu, M and Chen, J and Sun, Y},
title = {Mechanistic Insights into Elevated Caspase-8 Expression Driving Caspase-3 Activation and Gasdermin E-Dependent Pyroptosis in Alzheimer's Disease.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {114594},
doi = {10.1016/j.yexcr.2025.114594},
pmid = {40334809},
issn = {1090-2422},
abstract = {BACKGROUND: This study aims to investigate the specific mechanism by which caspase-8 regulates pyroptosis through Gasdermin E (GSDME) in Alzheimer's disease (AD). By analyzing the expression level of caspase-8 in AD pathology and its impact on pyroptosis and neuroinflammation, we aim to elucidate the role of caspase-8 as a potential therapeutic target and provide new insights into the pathological research and treatment strategies for AD.

METHODS: We utilized GEO2R to analyze the GSE48350 and GSE118553 datasets, identifying differential genes in AD and exploring the pathways involved through GO and KEGG enrichment analyses. The expression patterns of caspase-8 in different tissues and cells were analyzed using the HPA and UCSF databases. RT-qPCR and Western blot techniques were employed to detect the expression of caspase-8 and caspase-3 in AD cellular models. By knocking down caspase-8 and caspase-3, we observed their effects on the expression of pyroptosis-related proteins and inflammatory cytokines.

RESULTS: This study is the first to systematically reveal that caspase-8 is significantly upregulated in AD and induces pyroptosis by activating caspase-3, which mediates GSDME cleavage. In AD cellular models, knockdown of caspase-8 resulted in significant reductions in pyroptosis and cell death. Moreover, knockdown of caspase-3 significantly decreased the cleavage of GSDME and the expression of inflammatory cytokines IL-1β and IL-18.

CONCLUSION: This study demonstrates that caspase-8 is significantly upregulated in Alzheimer's disease (AD) and exacerbates neuroinflammation and cell death through the activation of caspase-3 and Gasdermin E (GSDME)-dependent pyroptosis. Inhibition of caspase-8 effectively alleviates AD pathological changes, highlighting its potential as a therapeutic target.},
}

@article {pmid40334339,
year = {2025},
author = {Tan, H and Fu, X and Yang, R and Tang, J and Zeng, S and Liu, Z and Zhu, X and Zhang, X and Xie, L and Wu, D},
title = {Dual targeting of FSP1 and xCT: Potential mechanism of anthocyanins in alleviating neuronal ferroptosis in vascular dementia.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {142},
number = {},
pages = {156608},
doi = {10.1016/j.phymed.2025.156608},
pmid = {40334339},
issn = {1618-095X},
abstract = {BACKGROUND: VaD, the second most prevalent type of dementia in the elderly following Alzheimer's disease, is marked by significant cognitive and motor deficits, with few effective treatment options currently available. Ferroptosis, a type of regulated cell death driven by iron-mediated lipid peroxidation, has recently emerged as a key pathological mechanism in the development of VaD. Ferroptosis drives neuronal damage in VaD, making it a promising therapeutic target to reduce neuronal death and preserve cognitive function. ACN, a group of polyphenolic compounds recognized for their strong antioxidant properties, have demonstrated potential in reducing ferroptosis and alleviating neuronal damage.

OBJECTIVE: The aim of this study was to explore the neuroprotective effects of ACN in reducing ferroptosis and mitigating cognitive impairments associated with VaD, focusing on the dual modulation of the FSP1 and xCT/GPX4 pathways. This novel dual-target approach provides an innovative strategy to reduce neuronal damage and oxidative stress in VaD.

METHODS: A combination of in vitro and in vivo experiments was conducted to assess the protective effects and underlying mechanisms of ACN in mitigating ferroptosis associated with VaD. In vitro, a neurotoxicity model was established by inducing PC12 cells with Glu. Cell viability was determined using the CCK-8 assay, and various markers, including ROS levels, MDA, LPO, and GSH levels, were measured to evaluate the protective effects of ACN. Additionally, the expression of ferroptosis-related proteins, such as FSP1, xCT, and GPX4, was analyzed through Western blotting, RT-qPCR, and immunofluorescence. In vivo, a VaD rat model was established by performing bilateral common carotid artery occlusion (2-VO). The rats were divided into four groups: control, model, ACN-treated (with varying doses), and ALA-treated (positive control). The intervention lasted for 28 days. Cognitive functions were assessed using the Morris water maze and novel object recognition tests. Histological analyses, including HE staining and Nissl staining, were carried out to examine neuronal pathology. Moreover, electron microscopy was employed to evaluate mitochondrial ultrastructure integrity. Brain levels of iron, lipid peroxidation markers, and the expression of FSP1, xCT, and GPX4 were measured to elucidate the molecular mechanisms underlying the observed effects.

RESULTS: Systematic in vitro and in vivo experiments demonstrated the significant neuroprotective effects of ACN against ferroptosis associated with VaD. In the Glu-induced PC12 cell model, ACN significantly improved cell viability, reduced ROS levels, restored GSH levels, and decreased the accumulation of MDA and LPO. Notably, ACN upregulated the expression of key ferroptosis-suppressing proteins, FSP1, xCT, and GPX4, through dual activation of these pathways, highlighting its powerful protective role against oxidative stress and ferroptosis. In the 2-VO VaD rat model, high-dose ACN significantly improved cognitive function, as shown by reduced escape latency in the Morris water maze and increased platform crossings. Moreover, ACN treatment enhanced the discrimination index in the novel object recognition test, suggesting improved learning and memory. Histopathological analyses revealed that ACN significantly alleviated neuronal disorganization, increased Nissl body counts, and restored mitochondrial integrity, with reduced swelling, rupture, and vacuolation observed under electron microscopy.

CONCLUSION: ACN exerts significant neuroprotective effects in VaD by dual regulation of the FSP1 and xCT/GPX4 pathways, effectively inhibiting ferroptosis and alleviating oxidative stress. This "dual-target" mechanism not only expands the current understanding of ACN's neuroprotective effects but also emphasizes its unique role in inhibiting ferroptosis. Overall, this study provides experimental evidence supporting the potential use of ACN in treating ferroptosis-related neurodegenerative diseases and highlights its promising prospects for clinical application.},
}

@article {pmid40332804,
year = {2025},
author = {Xing, H and Yue, S and Qin, R and Du, X and Wu, Y and Zhangsun, D and Luo, S},
title = {Recent Advances in Drug Development for Alzheimer's Disease: A Comprehensive Review.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083905},
pmid = {40332804},
issn = {1422-0067},
support = {2022YFE0132700//Major Intergovernmental Joint Research Project of National Key R & D Program of China/ ; GUIKE AA25069003//"Dai Tu Yi Zhi" Project of Key R & D Program of Guangxi/ ; 82320108019//Major International Joint Research Project of National Natural Science Foundation of China/ ; 42376112//the National Natural Science Foundation of China/ ; 82360698//the National Natural Science Foundation of China/ ; 2024GXNSFDA999003//Key Project of Natural Science Foundation of Guangxi/ ; D20010//the 111 Center/ ; YCSW2024067//Innovation Project of Guangxi Graduate Education/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Drug Development ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive impairments such as memory loss and executive dysfunction. The primary pathological features of AD include the deposition of amyloid-beta (Aβ) plaques, the hyperphosphorylation of tau proteins leading to neurofibrillary tangles, disruptions of neuronal and synaptic functions, and chronic inflammatory responses. These multifactorial interactions drive disease progression. To date, various therapeutic agents targeting these pathological mechanisms have been developed. This article provides a comprehensive review of the pathogenesis of AD, recent advances in drug development targeting different pathways, current challenges, and future directions, aiming to offer valuable insights for clinical treatment and research.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
*Drug Development
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Animals

@article {pmid40332773,
year = {2025},
author = {Yang, YP and Nicol, CJB and Chiang, MC},
title = {A Review of the Neuroprotective Properties of Exosomes Derived from Stem Cells and Exosome-Coated Nanoparticles for Treating Neurodegenerative Diseases and Stroke.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083915},
pmid = {40332773},
issn = {1422-0067},
support = {NSTC 113-2314-B-030-007, NSTC 113-2515-S-030-001, and NSTC 114-2918-I-030-001//National Science and Technology Council/ ; },
mesh = {*Exosomes/metabolism/chemistry ; Humans ; *Neurodegenerative Diseases/therapy/drug therapy/metabolism ; *Nanoparticles/chemistry ; Animals ; *Stroke/therapy/drug therapy/metabolism ; *Stem Cells/metabolism/cytology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Drug Delivery Systems ; Blood-Brain Barrier/metabolism ; },
abstract = {Neurological diseases, including neurodegenerative disorders and stroke, represent significant medical challenges due to their complexity and the limitations of current treatment approaches. This review explores the potential of stem cell (SC)-derived exosomes (Exos) as a transformative therapeutic strategy for these diseases. Exos, especially those derived from SCs, exhibit natural targeting ability, biocompatibility, and the capacity to cross the blood-brain barrier (BBB), making them ideal vehicles for drug delivery. This review provides an in-depth discussion of the properties and advantages of SC-Exos. It highlights their potential synergistic benefits in therapeutic approaches to treat neurological diseases. This article discusses the mechanisms of action of SC-Exos, highlighting their ability to target specific cells, modulate disease pathways, and provide controlled release of therapeutic agents. Applications in specific neurological disorders have been investigated, demonstrating the potential to improve outcomes in conditions such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and stroke. Moreover, Exos-coated nanoparticles (NPs) combine the natural properties of Exos with the multifunctionality of NPs. This integration takes advantage of exosome membrane biocompatibility and targeting capabilities while preserving NPs' beneficial features, such as drug loading and controlled release. As a result, Exos-coated NPs may enhance the precision, efficacy, and safety of therapeutic interventions. In conclusion, SC-Exos represent a promising and innovative approach to treating neurological diseases.},
}

*Exosomes/metabolism/chemistry
Humans
*Neurodegenerative Diseases/therapy/drug therapy/metabolism
*Nanoparticles/chemistry
Animals
*Stroke/therapy/drug therapy/metabolism
*Stem Cells/metabolism/cytology
*Neuroprotective Agents/therapeutic use/pharmacology
Drug Delivery Systems
Blood-Brain Barrier/metabolism

@article {pmid40332446,
year = {2025},
author = {Reynoso-García, MF and Nicolás-Álvarez, DE and Tenorio-Barajas, AY and Reyes-Chaparro, A},
title = {Structural Bioinformatics Applied to Acetylcholinesterase Enzyme Inhibition.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083781},
pmid = {40332446},
issn = {1422-0067},
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; *Acetylcholinesterase/chemistry/metabolism ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Humans ; *Computational Biology/methods ; Ligands ; Protein Binding ; Drug Discovery ; Alzheimer Disease/drug therapy ; },
abstract = {Acetylcholinesterase (AChE) is a critical enzyme involved in neurotransmission by hydrolyzing acetylcholine at the synaptic cleft, making it a key target for drug discovery, particularly in the treatment of neurodegenerative disorders such as Alzheimer's disease. Computational approaches, particularly molecular docking and molecular dynamics (MD) simulations, have become indispensable tools for identifying and optimizing AChE inhibitors by predicting ligand-binding affinities, interaction mechanisms, and conformational dynamics. This review serves as a comprehensive guide for future research on AChE using molecular docking and MD simulations. It compiles and analyzes studies conducted over the past five years, providing a critical evaluation of the most widely used computational tools, including AutoDock, AutoDock Vina, and GROMACS, which have significantly contributed to the advancement of AChE inhibitor screening. Furthermore, we identify PDB ID: 4EY7, the most frequently used AChE crystal structure in docking studies, and highlight Donepezil, a well-established reference molecule widely employed as a control in computational screening for novel inhibitors. By examining these key aspects, this review aims to enhance the accuracy and reliability of virtual screening approaches and guide researchers in selecting the most appropriate computational methodologies. The integration of docking and MD simulations not only improves hit identification and lead optimization but also provides deeper mechanistic insights into AChE-ligand interactions, contributing to the rational design of more effective AChE inhibitors.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology
*Acetylcholinesterase/chemistry/metabolism
Molecular Docking Simulation
Molecular Dynamics Simulation
Humans
*Computational Biology/methods
Ligands
Protein Binding
Drug Discovery
Alzheimer Disease/drug therapy

@article {pmid40332373,
year = {2025},
author = {Cui, XM and Wang, W and Yang, L and Nie, BW and Liu, Q and Li, XH and Duan, DX},
title = {Acanthopanax Senticosus Saponins Prevent Cognitive Decline in Rats with Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083715},
pmid = {40332373},
issn = {1422-0067},
support = {222102310143//Henan Province Science and Technology Research Project/ ; },
mesh = {Animals ; *Eleutherococcus/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Cognitive Dysfunction/drug therapy/prevention & control/metabolism ; *Saponins/pharmacology/chemistry/therapeutic use ; Male ; Hippocampus/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; tau Proteins/metabolism ; Maze Learning/drug effects ; NF-kappa B/metabolism ; Streptozocin ; },
abstract = {Alzheimer's disease (AD) is a progressive degenerative disease of the nervous system that affects older adults. Its main clinical manifestations include memory loss, cognitive dysfunction, abnormal behaviour, and social dysfunction. Neuroinflammation is typical in most neurodegenerative diseases, such as AD. Therefore, suppressing inflammation may improve AD symptoms. This study investigated the neuroprotective effects of Acanthopanax senticosus saponins (ASS) in an AD model induced by streptozotocin (STZ). Here, we characterised a rat model of STZ-induced AD with the parallel deterioration of memory loss and neuroinflammation. Following the end of the treatment with ASS (50 mg/kg for 14 consecutive days), behavioural tests (Morris water maze test, Y-maze test) were performed on the rat, and the molecular parameters (DAPK1, Tau5, p-Tau, NF-κB, IL-1β, TNF-α, and NLRP3) of the rat hippocampus were also assessed. We demonstrated that ASS, which has potent anti-inflammatory effects, can reduce neuroinflammation and prevent cognitive impairment. In the water maze test, ASS-treated groups exhibited significantly increased average escape latency (p < 0.05), the percentage of stay in the target quadrant (p < 0.05), and the number of times each group of rats crossed the platform (p < 0.05) compared to the negative control. And ASS could reduce the phosphorylation of the Tau protein (p < 0.001) and death-associated protein kinase 1 (DAPK1, p < 0.001) in the hippocampal tissue, improving cognitive impairment in STZ-treated rats by suppressing the inflammatory response; the molecular analysis showed a significant reduction in pro-inflammatory markers like NLRP3, IL-1β, TNF-α, and NF-κB (p < 0.001). It was also discovered that the NF-κB inhibitor SN50 had the same effect. Therefore, the present study used ASS through its anti-inflammatory effects to prevent and treat AD. This study highlights the potential efficacy of ASS in alleviating cognitive dysfunction in AD.},
}

Animals
*Eleutherococcus/chemistry
*Alzheimer Disease/drug therapy/metabolism
Rats
*Cognitive Dysfunction/drug therapy/prevention & control/metabolism
*Saponins/pharmacology/chemistry/therapeutic use
Male
Hippocampus/drug effects/metabolism
*Neuroprotective Agents/pharmacology
Disease Models, Animal
tau Proteins/metabolism
Maze Learning/drug effects
NF-kappa B/metabolism
Streptozocin

@article {pmid40332288,
year = {2025},
author = {Bao, X and Zhang, C and Ren, Z and Wang, Y and Zeng, L},
title = {Multi-Omics Integration Analysis Revealed That miR-375-3p Is a Two-Sided Factor Regulating the Development and TUMORIGENESIS of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083666},
pmid = {40332288},
issn = {1422-0067},
support = {YDZJ202301ZYTS536//the Science and Technology Department of Jilin Province/ ; },
mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; Protein Interaction Maps/genetics ; Small Cell Lung Carcinoma/genetics/pathology/metabolism ; Gene Expression Regulation, Neoplastic ; Lung Neoplasms/genetics/pathology/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; *Carcinogenesis/genetics ; Gene Regulatory Networks ; Tumor Microenvironment/genetics ; Gene Expression Profiling ; Multiomics ; },
abstract = {It has been reported that miR-375-3p plays a critical role in numerous diseases. To elucidate its biological function, particularly its differential expression and specific mechanisms of action in Alzheimer's disease (AD) and small cell lung cancer (SCLC), this study comprehensively explores the associations between the target genes of miR-375-3p and both AD and SCLC. The focus is specifically on its impact on disease progression and the remodeling of the tumor microenvironment. We utilized databases such as the miRNA TargetScanHuman 8.0 database and the STRING database, to construct a protein-protein interaction (PPI) network for the classification and discrimination of the miR-375-3p gene, resulting in the identification of 14 intersecting target genes. Subsequently, two key genes, ASCL1 and CHD7, along with their associated genes, were further analyzed using Spearman correlation analysis. The identified key genes were then subjected to GO function annotation and KEGG pathway enrichment analysis. It was determined that pathways related to lipid metabolism, autophagy, and cell apoptosis were differentially expressed in the AD and SCLC environments, with nine related pathways identified, among which the PI3K pathway was the most prominent. Finally, we demonstrated that the expression of miR-375-3p significantly differed between the two environments, with higher expression levels observed in AD compared to SCLC. Our study confirmed that miR-375-3p can promote apoptosis, regulate lipid metabolism, influence the progression of neurodegenerative diseases, and inhibit the proliferation and metastasis of tumor cells. These research findings may have significant implications for the future treatment of AD and SCLC.},
}

*MicroRNAs/genetics/metabolism
Humans
*Alzheimer Disease/genetics/pathology/metabolism
Protein Interaction Maps/genetics
Small Cell Lung Carcinoma/genetics/pathology/metabolism
Gene Expression Regulation, Neoplastic
Lung Neoplasms/genetics/pathology/metabolism
Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism
*Carcinogenesis/genetics
Gene Regulatory Networks
Tumor Microenvironment/genetics
Gene Expression Profiling
Multiomics